Université Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie,
5 rue J.-B. Clément, Châtenay-Malabry, F-92296, France
(* Corresponding authors)
The 90-kDa heat shock protein 90, Hsp90, belongs to the family of molecular chaperone responsible for the conformational maturation or reparation of other proteins, referred to as "clients", into biologically active structures (Pearl and Prodromou, 2006). Hsp90 exerts its essential ATP dependant chaperone function to more than three hundred client proteins involved in cell growth, differentiation and survival (Workman, 2004; Chiosis et al., 2004; Sreedhar et al., 2004b; Zhang and Burrows, 2004; Neckers, 2002). Many of them, more than forty, include overexpressed or mutant oncogenic proteins ErbB2/HER2 (Miller et al., 1994; An et al., 1997), Braf (Grbovic et al., 2006), Akt/PKB (Sato et al., 2000), muted p53 (Blagosklonny et al., 1996), transcription factors: hormone steroid receptors GR (Grad and Picard, 2007) ER and AR, angiogenic factors HIF-1α (Picard, 2006; Kuduk et al., 2000; Kuduk et al., 1999; Johnson and Toft, 1995), telomerase (Forsythe et al., 2001; Akalin et al., 2001) which are associated with the six hallmarks of cancer (Figure 1).
Under non-stress conditions the quaternary structure of Hsp90 is now well established to be a dimeric complex, and its abundance is approximately 1% of the total protein contents. Each monomer consists in three domains: the N-terminal domain (NTD), a middle domain (MD) implicated in client protein binding, and a C-terminal dimerization domain (CTD) (Figure 2) (Harris et al., 2004; Shiau et al., 2006).
In the human proteome, several isoforms of Hsp90 have been isolated, Hsp90α (inducible form) and Hsp90β (constitutive form) localized in cytoplasm (Sreedhar et al., 2004a), while Grp94 (glucose-regulated protein) and TRAP-1 (HSP75/tumor necrosis factor receptor associated protein 1) are localized in the endoplasmic reticulum and in mitochondria respectively (Csermely et al., 1998; Maloney and Workman, 2002). To acquire its full active molecular chaperone activity, Hsp90 operates with molecular co-chaperones and partner proteins to form a series of multimeric protein complexes (Figure 3) including Hsp70, peptidyl-prolyl isomerases, immunophilins (FKBP51 and FKBP52) and the cyclophilin CYP40. Others co-chaperones such as p23, recently identified as a prostaglandine E2-Syntase, plays an important role in the activity of a number of transcription factors of the steroid/thyroid receptor family (Chan et al., 2008; Grad et al., 2006).
It is now well established, that Hsp90 needs to bind ATP in a pocket located in the N-terminal domain to exert its function. Thus, the Hsp90 protein function may be inhibited by molecules competing with ATP binding (such as geladanamycin: GA, Figure 3), thereby freezing the chaperone cycle, which in turn decreases the affinity of Hsp90 for client proteins and leads to 26S proteasome-mediated oncogenic client protein degradation (Sepp-Lorenzino et al., 1995). N-terminal domain Hsp90 inhibitors block cancer cell proliferation in vitro and cancer growth in vivo (Sharp and Workman, 2006).
To date, the full crystal structure of Hsp90 in complex with a non hydrolysable ATP analogue (Ali et al., 2006), and of the full length E.Coli Hsp90 without nucleotide (apo-Hsp90) (Shiau et al., 2006), have yet been reported (Figure 2). Furthermore, an interesting recent study investigated Hsp90 conformational changes in solution, shows a long range effects between Hsp90 domains, as the binding of co-chaperones (or inhibitors) at NTD induce conformational changes in the MD and CTD (Phillips et al., 2007). The C-terminal domain has been implicated biochemically as the site of a possible second, cryptic ATP-binding site on Hsp90. Its contribution to the overall regulation of chaperone function is not clear, but the antibiotic novobiocin (Nvb) (c.f. structure in Figure 15) has been reported to bind this site and alter the conformation of the chaperone (Yun et al., 2004).
Since pharmacological inhibition of Hsp90 by several families of small molecules leading to the degradation of oncogenic proteins, Hsp90 has become a target of interest against cancer and allowed the development of numerous small inhibitors (Biamonte et al., 2010).
II) Hsp90 health and cancer (Powers and Workman, 2007)
Hsp90 has probably been most widely acknowledged as a therapeutic target for the treatment of cancer (Mitsiades et al., 2007). Although there is no evidence of Hsp90 mutations in malignancy, there is increasing support for the view that this molecular chaperone plays an important role in the development, maintenance and progression of cancers.
One of the principal debates concerning the inhibition of the highly abundant Hsp90 is the selectivity of inhibitors for the chaperone protein in malignant cells (Kamal et al., 2003). Some works suggest that Hsp90 inhibitors could provide an exploitable therapeutic index (Banerji, 2005). Firstly, it has been reported that inhibitors were significantly more sensitive to Hsp90 in cancer cells (Neckers and Neckers, 2005; Powers and Workman, 2006; Chiosis, 2006; Whitesell et al., 1994; Neckers, 2006). In support to this surprising observation, Kamal et al. showed that the activity state of the Hsp90 chaperone machine was different in tumor cells. Indeed, the Hsp90 is entirely bound in an active complex with co-chaperones, whereas most Hsp90 in normal tissues resides in a free, uncomplexed state (Workman, 2004; Kamal et al., 2003). Furthermore, Hsp90 is constitutively expressed at higher levels (2-10 fold) in tumor cells compared with their normal counterparts. This higher Hsp90 activity is probably due to the overexpression/amplification of mutated Hsp90 clients, and this is in correlation with the higher level of cochaperones of Hsp90 observed in cancerous cells.
Finally, the selective sensitivity of transformed cells for Hsp90 inhibitors may be partly due to the selective accumulation of these drugs in cancer cells since the in vivo observation of Hsp90 inhibitors in murine model system showed higher concentration in tumor tissue (Chiosis and Neckers, 2006).
Consequently, the Hsp90 has emerged as an exciting target for the development of cancer chemotherapeutics. However, despite the numerous molecules which have prompted a phase I clinical trial, it remains to be verified if Hsp90 inhibitors will provide adequate treatment in clinic.
III) Hsp90 inhibitors (Messaoudi, 2008)
The Hsp90 protein function may be inhibited with molecules that bind the ATP pocket, or its chaperone activity may be disturbed by small molecules binders interfering with domains in the C-terminus or median region. Although Hsp90 function provides an attractive target for the treatment of cancer, the feasibility and efficacy of the inhibitors approach has just begun to be explored in clinic.
Direct inhibitors of Hsp90 have been divided into two groups:
A) N-terminal domain binders
1) Ansamycin macrolactames
1.a) Quinone derivatives
Geldanamycin (Figure 4), was isolated from the broth of Streptomyces hygroscopicus in 1970s (De Boer et al., 1970). Further studies have shown that GA revert the phenotype of v-src oncogene transformed cells. However, this ability was not due to a direct action of the Src kinase activity, but to an inhibition of Hsp90. Subsequent immunoprecipitation and X-ray cristallographic studies have shown that GA competes with ATP and binds to the N-terminal domain site of Hsp90, leading the Hsp90 multichaperone complexes to the ubiquitin-mediated proteasome degradation (Roe et al., 1999; Stebbins et al., 1997). Since this observation, GA was used to identify additional Hsp90 substrates and to understand the role of Hsp90 in promoting malignant transformation. Although GA provided very promising antitumor effects, it showed several pharmacologic limitations as poor solubility, limited in vivo stability and high hepatotoxicity in some of the human tumor models (Neckers, 2006; Supko et al., 1995). Thus, the 17-position of GA has been an attractive focal point for the synthesis of GA analogues. Structure-activity relationship (SAR) studies have shown that structurally and sterically diverse 17-substituents can be introduced without destroying antitumor activity. Then, further derivatives of GA, with similar biological behaviour but a better toxicity profile, were synthesized (Schulte and Neckers, 1998). Therefore, new C-17 substituted derivatives 17-AAG (17-allyl-17-desmethoxygeldanamycin, also designed KOS953, CNF 1010, tanespimycin, Figure 4) and 17-DMAG (17-(2-dimethylaminoethylamino)-17-desmethoxygeldanamycin, KOS1022, alvespimycin, Figure 4) (Snader et al., 2002; Solit et al., 2007) were brought to the fore by displaying a significant enhancement of the chemical/metabolic stability.
17-AAG can be used in single agent or in combination with other cancer therapeutics (KOS953/bortezomib (Anderson, 2007; Richardson et al., 2007), KOS953/trastuzumab (Modi et al., 2007), 17-AAG/Paclitaxel (Sain et al., 2006), 17-AAG/cisplatin (McCollum et al., 2008)).
To enhance the pharmacokinetics and dynamics of 17-AAG, Kosan Biosciences Incorporated has developed a DMSO-free formulation (KOS953) contained cremophor, which is actually in Phase I clinical testing.
Although 17-AAG and its numerous formulations have shown some encouraging clinical responses, they present important drawbacks (e.g.; liver toxicity and cumbersome formulation) that may limit their clinical applications whereas 17-DMAG exhibits a better water solubility and oral bioavailability (Ronnen et al., 2006). However, although clinical trials in myeloid leukemia seemed to be promising, the 17-DMAG was discontinued in 2008 (ClinicalTrials.gov).
1.b) Hydroquinone derivatives
In a different approach, Infinity Pharmaceuticals has developed IPI504 (retaspimycin or 17-AAG hydroquinone, Figure 4) (Adams et al., 2005; Sydor et al., 2006), a new GA analogue, in which the quinone moiety was replaced by a dihydroquinone one. Indeed, the preclinical data suggested that the hepatotoxicity of 17-AAG was attributable to the ansamycin benzoquinone moiety, prone to nucleophilic attack. Furthermore, it was recently reported that the hydroquinone form binds Hsp90 with more efficiency than the corresponding quinone form (Maroney et al., 2006). In biological conditions, the hydroquinone form can interconvert with GA, depending on redox equilibrium existing in cell. It has been recently proposed, that NQ01 (NAD(P)H: quinone oxidoreductase) can produce the active hydroquinone from the quinone form of IPI504 (Chiosis, 2006). However, Infinity Pharmaceuticals showed that if the overexpression of NQ01 increased the level of hydroquinone and cell sensitivity to IPI504, it has no significant effect on its growth inhibitory activity. These results suggest that NQ01 is not a determinant of IPI504 activity in vivo (Douglas et al., 2009).
1.c) Clinical trials
In 2007, results of the phase I clinical trial of tanespimicyn (KOS953) with bortezomib in patients with relapsed refractory multiple myeloma were reported (Solit and Chiosis, 2008; Taldone et al., 2008). Dose escalations in the trial ranged from 100 to 340 mg/m2 for tanespimycin, and from 0.7 to 1.3 mg/m2 for bortezomib. Results showed that two patients, on the 41 enrolled, exhibited stable disease after two cycles, and 18 of them demonstrated a response to combination (Richardson et al., 2007). Moreover, the tanespimicyn was co-administrated with trastuzumab on 25 patients treated with up to 450 mg/m2 of drug on a weekly schedule. This combination induced a regression of 21, 22 and 25% in three patients, which had failed trastuzumab therapy, with HER2-amplified breast cancer (Modi et al., 2007).
In 2008, Infinity Pharmaceuticals reported the results of a dose escalation Phase I/II clinical trial of retaspimycin hydrochloride in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) on a twice weekly schedule (400 mg/m2). 4 of the 18 patients enrolled, achieved a partial response and 11/18 achieved stable disease. These results had initiated the phase III clinical trial of the study in 2008. However, Infinity Pharmaceuticals reported on April 2009, the decision to end its phase III study (RING trial) of IPI504 hydrochloride in patients with refractory gastrointestinal stromal tumors (Infinity Press Release). The trial was based on 46 patients whose tumors persist despite treatment with Gleevec (imatinib) and Sutent (sunitinib). Resulting data showed a higher than anticipated mortality rate. In this heavily pretreated population, IPI504 was not tolerated (400 mg/m2 or placebo in 21 days cycles as a 30 min intravenous infusion twice weekly for 2 weeks followed by a 1 week rest) and the study was terminated early.
Nevertheless, the IPI504 is still evaluating in phase II trials in patients with non-small cell lung cancer, and in combination with herceptin (trastuzumab) in patients with HER-2 positive metastatic breast cancer.
In the same month, KOSAN, acquired by BMS in 2008, reported that the phase III clinical trial concerning the KOS953 or tanespimycin, in combination with Bortezomib in patients with multiple myeloma in first relapse has been suspended. This was probably a precaution as the metabolization of tanespimycin leads to IPI504.
Conforma Therapeutics/Biogen idec developed a hydroquinone form of the 17-AAG (CNF1010), trapped as HCl salt, which was in clinical phase I against chronic lymphocytic leukemia. However, to date, this program is terminated. Moreover, the CNF1010 had started a phase III trial against GIST in 2008. This study was also suspended due to the anticipated mortality rate of patients enrolled (ClinicalTrials.gov). Parallel efforts to improve the solubility and bioavailability of 17-AAG have led the NCI and Kosan to develop 17-DMAG (KOS1022) as a second generation alternative which has entered Phase I clinical testing (Santi et al., 2007). Promising results were obtained in patients with chemotherapy refractory acute myelogenous leukemia, as 3 of 17 patients had a complete response to therapy (Lancet et al., 2006). However, researches were given up in 2008, as the 17-DMAG presents an unusable toxicity profile.
1.d) Other analogues
Diverse derivatives of 17-AAG bearing non-redox-active phenol group designed by Kosan Biosciences were reported (Tian et al., 2007). Amongst them, KOSN1559 was claimed as the most potent Hsp90 inhibitor (e.g.; SKBr3 Cell Line IC50=860 nM, Kd=16 nM) (Figure 5). To date, no clinical trial had been reported with this compound.
2.a) Purines analogues
Limitations in the clinical use of 17-AAG and 17-DMAG have prompted the discovery of novel Hsp90 ATPase inhibitors with improved "drug-like" structural characteristics and better pharmacological profiles. To this end, structure-based design and high-throughput screening approaches performed at the Memorial Sloane Kettering Institute, have been taken to identify new chemotypes that inhibit Hsp90 ATPase activity. A significant breakthrough in the preparation of synthetic Hsp90 inhibitor was the PU3 (Figure 6). On the basis of X-ray analysis and molecular modelling, Chiosis's group, showed that PU3 was designed to place the purine moiety into the same spatial orientation as adenine ring of ATP in the nucleotide pocket of Hsp90 (Chiosis et al., 2001). PU3 presented molecular signature of Hsp90 inhibition, including the degradation of HER2, even if its affinity for Hsp90 is moderate.
Chiosis's group and Conforma therapeutics/Biogen Idec optimized this class of compounds leading to new analogues bearing a thioether bridge to connect the purine nucleus to substituted phenyl rings. Among them, the PUH58 (Figure 7) (Llauger et al., 2005), an 8-arylsulfanyl analogue of PU3, has been identified as the most potent and selective purine. Further efforts in optimization of this lead compound led to the development of PU24F-Cl, (Figure 7) which presents a higher affinity (30 times more than PU3) for the N-terminus of the Hsp90, and low micromolar activity in a cell proliferation assay (Chiosis et al., 2002; Vilenchik et al., 2004). In an in vivo experiment in MCF-7 tumor bearing mice, PU24FCl led to 70% inhibition when administered at a dose of 200 mg/kg every second day for 30 days (Vilenchik et al., 2004).
Additional investigations concerning the pharmacophore of this family were done. It was demonstrated that the presence of an amino group on the C2 position of the purine nucleus respects the global size of the molecule in regard to the parent one (PU3). In addition, it offers multiple possibilities for hydrogen bonding, and thus allowed the connection of the benzyl group on the N-9 rather than the C-8 of the purine. Thus, Conforma-Biogen idec have identifed the BIIB021 (originally named CNF 2024, Figure 7) (Kasibhatla et al., 2007) which displayed a binding affinity of 1.7 nM (4.6 nM for 17-AAG) and induces degradation of HER2 with an IC50 of 38 nM in MCF-7 cells (Lundgren et al., 2009). BIIB021 compound was entered in clinical trials in 2005.
2.b) Clinical trial
Currently, BIIB021 is the only purine analogue evaluated in phase I/II clinical trials in combination with trastuzumab (herceptin) against breast cancer, with an aromatase inhibitor (exemestane) in metastatic HER2-advanced breast cancer, or alone in subjects with gastrointestinal stromal tumors. Results from the phase I trials showed that BIIB021 was well tolerated (800 mg twice weekly) and induced a significant inhibition of the HER2 (Elfiky et al., 2008).
3) Pyrazole and isoxazole derivatives
3.a) Pyrazole analogues
In 2004, CCT018159 (Figure 8), the first Hsp90 inhibitor in the pyrazole series, was identified by Workman et al. from a library of 60000 compounds, using a high throughput screening (HTS), in the Cancer Research UK Centre for Cancer Therapeutics (Rowlands, 2004). This compound inhibits the N-terminal ATPase activity of yeast and human Hsp90 with an IC50 of 7.1 and 3.2 µM, respectively (Cheung et al., 2005; Sharp et al., 2007a). Further HTS studies undertaken by Genomics institute of the Novartis Research Foundation (GNF) and based on time-resolved fluorescence resonance energy transfer (TR-FRET) had allowed identifying two leads, G3129 and G3130 (Figure 8), amongst the one million molecules screened (Kreusch et al., 2005). However, both compounds exhibited relatively poor binding affinity to N-terminal domain of the Hsp90 (Kd=680 and 280 nM respectively). In SkBr3 breast cancer cells, G3130 caused the degradation of HER2 (IC50=30 µM) while G3129 was ineffective.
In addition, the co-crystal structures of G3129 and G3130, bound to the N-terminus of human Hsp90α, were reported (Kreusch et al., 2005). From this study, it was showed that the resorcinol ring bound Hsp90 in a similar way than that of radicicol, a resorcylic lactone that inhibits Hsp90.
Furthermore, the 5-ethyl appendage projected into the aromatic pocket that accommodates the benzyl group of the purine analogues described before. The pyrazole provides hydrogen bound acceptor, and the imidazole (G3130) occupies the same pocket as the quinone of GA (Figure 9).
Based on these data, medicinal chemistry efforts led to the identification of the more potent analogue of CCT018159, the VER49009 (IC50 ATPase activity=0.14 µM, Figure 10), where the amide group was a key in forming a new interaction with the residue Gly97 of the protein (Dymock et al., 2005).
Synta Pharmaceuticals Corp. had reported another class of triazoles analogues as modulators of Hsp90 (Figure 11) (Ying et al., 2009). It has been shown that STA-9090, an unspecified new resorcinol-containing triazole compound (Lin et al., 2008), inhibits the activity of Hsp90 protein from 10 to 100 µM and thereby leading to degradation of Hsp90 client proteins such as HER2 gene product (Ying et al., 2009). More recently, it had been shown that the STA-1474, a highly soluble phosphate prodrug of STA-9090, exhibits very interesting biologic activity against osteosarcoma cell lines (McCleese et al., 2009).
3.b) Isoxazole analogues
Further optimization of potency, pharmakinetic and pharmacodynamic properties of VER49009, were undertaken by Vernalis Ltd. (in collaboration with Novartis) to offer a series of isoxazole resorcinol inhibitors. One of these was the VER50589 (Figure 10) which exhibited a higher affinity (Kd=5 nM) than VER49009 (Kd=78 nM) (Sharp et al., 2007b). Thus, the pyrazole to isoxazole switch does not affect the critical hydrogen bound of the pyrazole resorcinol unit that anchors this class of inhibitors to the Hsp90 NH2-terminal ATP site (Brough et al., 2008). Moreover, VER50589 also showed improved cellular uptake over VER49009.
Brough et al. from Vernalis, reported recently the identification of new diarylisoxazole compound VER52296 (Figure 12) (Brough et al., 2008; Eccles et al., 2008). The areas of interest for SAR studies were the 5' positon on the resorcinol ring, and the para substitution of the phenyl group on the isoxazole ring. It has been shown with the X-ray cristal structure, that the replacement of the chlorine, in regard to VER50589, by an isopropyl group, results in an additional hydrophobic interaction with Leu107 in the flexible lipophilic pocket of the N-terminal site of Hsp90. Additional hydrophobic interactions were also observed with Thr109 and Gly135 from the morpholine moiety present in VER52296/NVP-AUY922 (Figure 12). This latter, subsequently developed by Novartis, was found to be very potent in the Hsp90 Fluorescence Polarization binding assay (IC50=21 nM) and displays an average GI50 of 2-40 nM in antiproliferation assays against different human tumor cell lines (Brough et al., 2008). In addition, as evaluated by cassette dosing to mice bearing subcutaneous HCT116 human colon cancer, VER52296/NVP-AUY922 was retained in HCT116 xenograft tumors when administered i.p., at concentrations well above the GI50. Further in vivo characterization in a human colon cancer xenograft model, VER52296/NVP-AUY922, also inhibits tumor growth by ~50% when dosed at 50 mg/kg i.p. daily. Moreover VER52296/NVP-AUY922 induces the degradation of HER2 with an IC50 of 7 nM. In addition, VER52296/NVP-AUY922 was tested in several xenografts (colon, glioblastoma, breast, ovarian, prostate) and a therapeutic response was observed in each case (Cheung et al., 2005; Jensen et al., 2008; Eccles et al., 2008).
3.c) Clinical trials
The VER52296/NVP-AUY922 is the sole isoxazole analogue currently in phase I/II clinical trials as a single agent or in combination with bortezomib or dexamethasone, in patients with relapsed or refractory multiple myeloma. AUY922 is also used as a single agent, in advanced solid malignancies and efficacy in HER2+ or ER+ locally advanced or metastatic breast cancer patients. In this latter phase I/II trial, VER52296/NVP-AUY922 was intravenously administrated once a week schedule. The maximum dose reported is 54 mg/m2. At 40 mg/m2, VER52296 induces an up regulation (4-19 fold) of Hsp70 and a 20% reduction in soluble HER2 was achieved by 74% of patients.
Noteworthy, the STA9090 (Figure 11) is currently enrolling patients in several phase I/II clinical trials against solid tumor, myeloid leukemia, non-small cell lung cancer and gastrointestinal stromal tumor.
4) Dihydroindazolone derivatives
4.a) SNX2112 and SNX5422
In 2007, Serenex Inc./Pfizer had started a phase I clinical trial program for the SNX5422 (Figure 13).
Using a new screening platform, the compounds retained on the ATP-affinity column were analyzed by mass spectrometry leading to the identification of a poorly soluble analogue, SNX2112, which will become the glycine prodrug SNX5422. The SNX2112 showed higher activity to bind Hsp90 (Ki=1 nM) than that of 17-DMAG and induced the degradation of HER2 with an IC50 of 20 nM. Based on the observation that breast cancer cell lines with HER2 amplification are more sensitive to 17-AAG, the SNX2112 was tested using a panel of breast, lung, and ovarian cancer cell lines. In all cell lines studied, SNX2112 inhibited cell proliferation with IC50 ranging from 10 to 50 nmol/L. In contrast to 17-AAG, the sensitivity of cancer cell lines to SNX2112 in vitro did not correlate with the level of HER2 expression (Chandarlapaty et al., 2008; Huang et al., 2006). This compound uniformly targets both the pro-proliferation pathways driven by HER2 and ERK as well as the anti-apoptotic Akt pathway (Okawa et al., 2009). Indeed, it exhibits potent in vivo antitumor activity that extends significantly the effects observed with GA analogues.
4.b) Clinical trial
SNX-5422 is currently in a phase I clinical trial in treating patients with solid tumor or lymphoma that has not responded to treatment. SNX5422 is equally tested to treat solid tumor cancer and lymphomas, and, in subjects with refractory hematological and solid tumor malignancies. In 2008, results of a phase I dose-escalation study of SNX5422 reported that this compound was well tolerated at 21 mg/m2.
5) Other inhibitors
Another class of ATP Hsp90 inhibitors bearing a resorcinol moiety is radicicol (Rd) (Figure 14), a natural resorcylic lactone, isolated from the fungus Monocillium nordinii and Monosporium bonorden. Rd, also known as monorden, has been described to reverse the Src-transformed morphology of fibroblast (Whitesell et al., 1994). This effect was first attributed to the inhibition of the oncogenic Src (v-Src), and later proved to act as an inhibitor of Hsp90 despite its difference in structure to GA. Moreover, Rd was found to compete with GA for binding to the NTD of the chaperone, suggesting that Rd shares the geldanamycin binding site. This compound is a potent and specific inhibitor of the ATPase activity of Hsp90 with nanomolar affinity (Kd=19 nM). This causes destabilization of Hsp90 client proteins (v-Src, Raf-1, ErbB2 and Ras), many of which are essential for tumor cell growth. Although, the in vitro antitumoral activity of Rd is very promising however, its in vivo activity is very weak probably because of its chemical instability in serum and its rapid conversion into inactive metabolites due to the electrophilic nature of the dienone moiety.
Therefore, synthetic efforts have been directed to identify radicicol derivatives with improved in vivo activity (Proisy et al., 2006). To date, Kyowa Hakko described novel oxime-derivatives of Rd, including KF55823 and KF25706 (Soga et al., 2003) (Figure 14). Although these compounds exhibit potent antitumor activities in preclinical models and do not seem to cause hepatotoxicity, their clinical evaluations of these compounds has not been pursued.
B) C-terminal domain binders
In 1991, Csermely, Kahn and co-workers reported the presence of a C-terminal ATP binding site on Hsp90 which becomes accessible when the N-terminal Bergerat pocket is occupied (Sõti et al., 2002). A decade later, it has been shown that Nvb interacts with an ATP-binding domain in the C-terminus of Hsp90 (Marcu et al., 2000a). Biochemical studies on the CTD of Hsp90 have identified an allosteric regulation process with the N-terminus site, where the occupancy of one site blocks the interaction of the ligand with the other site (Garnier et al., 2002). The structure of the full length and middle and C-terminal construction of Hsp90 with different nucleotide states (apo, ATP) have shown that there is a hinge region between the middle and C-terminal region of Hsp90. The conformation of this region is dictated by the status of the nucleotide at the N-terminal site. This observation is in accordance with the allosteric regulation of ATP binding. It suggests that the putative secondary ATP site could be located at the immediate proximity of the hinge.
IV) Coumarin inhibitors
Coumarin group antibiotics, such as novobiocin (Nvb), coumermycin A1 (Kd=10 nM) and clorobiocin (Figure 15), are potent inhibitors of the bacterial ATP binding gyrase B, a type II DNA topoisomerase (Gormley et al., 1996). Their affinity for gyrase is considerably higher than that of modern fluoroquinolones. These antibiotics have been isolated from various Streptomyces species (Lanoot et al., 2002) and all possess a 3-amino-4-hydroxycoumarin moiety as a key structural feature.
Nvb is licensed as an antibiotic for clinical use (Albamycin; Pharmacia-Upjohn) and for the treatment of infections with multi-resistant gram-positive bacteria such as Staphylococcus aureus and S. epidermidis (Raad et al., 1995; Raad et al., 1998; Rappa et al., 2000). It had been demonstrated that the interaction of Nvb with Hsp90 induces alteration in the affinity of the chaperone for GA and Rd and causes in vitro and in vivo depletion of key regulatory Hsp90-dependant kinases including v-Src, Raf-1 and ErbB2 (e.g., ErbB2 in SkBr3 breast cancer cells ~700 µM). In addition, Nvb was found to bind the C-terminal nucleotide binding region of Hsp90, albeit with a lower affinity than with gyrase B. Moreover, Nvb disrupts the interaction of both the cochaperones p23 and HSC70 with the Hsp90 complex.
In 2005, the first attempt to improve the inhibitory activity of Nvb against Hsp90 was reported (Yu et al., 2005; Blagg et al., 2006). These authors have highlighted the crucial role of the noviose moiety at the 7-position of the coumarin ring for the biological activity. Compound A4 lacking the 4-hydroxyl of the coumarin moiety and containing an N-acetyl side chain in lieu of the benzamide was the most active compound. This compound was identified as Hsp90 inhibitor that induced degradation of Hsp90-dependent client proteins at 70-fold lower concentration than Nvb. Recently, in continuation of their structural modification studies, the same authors reported that 3'-descarbamoyl-4-deshydroxynovobiocin DHN2 (Figure 16) and compound KU135 (Shelton et al., 2009) proved to be a more effective and selective Hsp90 inhibitor (degradation of ErbB2 and p53 between 0.1 and 1.0 µM) (Burlison et al., 2006).
Our group reported a novel series of 3-aminocoumarin analogues (Le Bras et al., 2007a; Le Bras et al., 2007b) lacking the noviose moiety as a class of highly potent Hsp90 inhibitors. A representative example of this new class of inhibitors is 4TCNA (Figure 17) (Le Bras et al., 2007b).
In these analogues, the introduction of a tosyl substituent on C-4 position of coumarin nucleus (4TCNA) contributed to a significant extent for maximal activity despite weaker water solubility. Moreover, this lead has a particular implication in apoptotic process. Thus, 4TCNA promotes apoptosis through activation of caspases 7 and 8 in ER-positive MCF-7 human breast cancer cells, whereas in Ishikawa endometrial adenocarcinoma cells, it induced apoptosis that was associated with caspase activation and cleavage of PARP. Furthermore, characterization of its mode of action revealed that 4TCNA induced-cleavage of the p23, recently identified as a prostaglandine E2-Syntase, which plays an important role in activity of a number of transcription factors of steroids/thyroid receptors family. These results demonstrate that this new denoviose compound presents originality in regard to Nvb osidic derivatives already known.
In another study based on a simplified 3-aminocoumarin scaffold, we also demonstrated that 4-tosyl-7-deshydroxycyclonovobiocic acid (4TDHCNA) (Figure 17) (Radanyi et al., 2008), exhibit increased inhibitory activity against the Hsp90 protein folding process (MCF7 IC50=50 µM).
This result shows that removal of C7/C8 substituents is not detrimental for Hsp90 inhibitory activity and strongly enhances the capacity of 4DHTCNA to inhibit Hsp90. This compound was identified to be the most potent representative of the new family of simplified coumarins. Results from this study suggest that 4TDHCNA and 4TCNA, which exerted similar biological profile may be considered interesting compounds for the development of more potent novobiocin analogues.
More recently, results from our group allowed the identification of a new family of novobiocin analogues in which the coumarin unit has been replaced by a 2-quinoleinone moiety (unpublished results). The quinolone-scaffold represents a platform for the creation of easily synthesizable soluble molecules. Compound 4-tosyl-3[(chroman-6-yl) carboxylamino]-2-quinolon (4TCCQ, Figure 17) (IC50=5-8 µM) is 100-fold more potent than the parent natural compound (novobiocin) and 6-fold more active than the synthetic analogue 4TCNA. Additionally, 4TCCQ induces the degradation of ERα and strongly induces the cell death in MCF-7 breast cancer cell line.
Overall, these data provides compelling evidence for the continued development of novobiocin-based C-terminal domain Hsp90 inhibitors as promising alternative to N-terminal domain inhibitors.
V) HSP 90 in Alzheimer's disease
Hsp90, a molecular chaperone, has come into its own as a tantalizing target for cancer therapies. However, its important functions of stabilization, rematuration, disaggregation of many client proteins could be exploitable in others diseases.
Indeed, neurodegenerative diseases are characterized by the accumulation of misfolded proteins that results in plaque formation. These proteins rely upon HSP's for their refolding and viability. Recently, it was suggested that Hsp90 may play a crucial role in maintaining pathogenic changes that lead to neurodegenerative diseases (Luo et al., 2008). Furthermore, the inhibition of Hsp90 by 17-AAG derivatives and geldanamycin, induces the HSP induction via HSF-1 activation, resulting in neuroprotective activities. In the Alzheimer's disease, the most common tauopathy, in addition to β-amyloid deposition, there is an accumulation of abnormal species of hyperphosphorylated protein tau which leads to the formation of toxic neurofibrillary tangles (Luo et al., 2007; Dickey et al., 2007). This hyperphosphorylation is caused by abnormal kinases (CdK4, GSK-3β) activities resulting in dissociation of transformed tau from microtubules, aggregation and formation of neurofibrillary tangles which can block the synaptic transmission (Figure 18).
Thus, the decrease of hyperphosphorylated tau levels through refolding or degradation may provide a possible therapeutic strategy against AD. In this purpose, Dickey and Luo have presented evidence that the stability of p35, (neuronal activator of CdK4) and P301L mutant (most common mutation in Alzheimer disease) are maintaining by Hsp90.
Dou et al. 2007 reported that Hsp90 associates with GSK-3β, regulating its stability and function, preventing its degradation by the proteasome and so allowing the increase of tau hyperphosphorylation. Thus, the use of Hsp90 inhibitors leads to a destabilization of GSK-3β and to a decrease of hyperphosphorylated tau protein.
Dickey et al. 2007 demonstrated that CHIP (a tau ubiquitin ligase) is intimately linked to tau degradation following Hsp90 inhibition and that this process is specific for promoting degradation of only aberrant phosphorylated tau due to the fact that the Hsp90 complex, in AD brain, presents higher affinity for inhibitors than in unaffected brain tissue.
Recently, compound A4 (Figure 16) was found to exhibit significant protection against the Aβ-induced toxicity at low concentrations (Lu, 2009). These results suggest that novobiocin analogues may represent an effective class of novel compounds for treatment of AD.
Since the first discovery of natural analogues, GA and RD, the search for inhibitors of Hsp90 has generated considerable interest as evidenced by the number of compounds in clinical evaluations (Table 1). However, if the first clinical results were very encouraging, it seems that currently the development of Hsp90 inhibitors experiencing some difficulties, especially due to their toxicity. Stopping clinical trials of IPI504, which represented the most advanced HSP90 inhibitors, is the unfortunate illustration of that. Thus, many efforts are still needed in the understanding of the administration of these agents but also in the synthesis of new molecules. Moreover, the involvement of Hsp90 in other non-oncological diseases such as Alzheimer's disease shows the importance of acquiring new and more potent inhibitors with suitable pharmacological and pharmacokinetic profiles.
Table 1: Current clinical trials.
Condition: R: recruiting, ANR: active, not recruiting, C: completed, NYR: not yet recruiting, S: suspended, T: terminated. Therapy: ADL: Advanced Dedifferentiated Liposarcoma, AGC: Advanced Gastric Cancer, AM: Advanced Malignancies, AML: Acute Myeloid Leukemia, AST: Advanced Solid Tumors, BC: Breast Cancer, CLL: B-Cell Chronic Lymphotic Leukemia, CLL: Chronic Lymphocytic Leukemia, CML: Chronic Myelogenous Leukemia, ALL: Acute Lymphoid Leukemia, MM: Multiple Myeloma, MetM: Metastatic Myeloma, NSCLC: Non Small Cell Lung Cancer, PC: Prostate Cancer, GIST: Gastrointestinal Stroma Tumor, RRMM: Relapsed or Refractory Multiple Myeloma, ST: Solid Tumors, UST: Unresectable Solid Tumors.
|Geldanamycin, a new antibiotic.|
|DeBoer C, Meulman PA, Wnuk RJ, Peterson DH.|
|J Antibiot (Tokyo). 1970 Sep;23(9):442-7.|
|The 90-kDa heat shock protein (hsp-90) possesses an ATP binding site and autophosphorylating activity.|
|Csermely P, Kahn CR.|
|J Biol Chem. 1991 Mar 15;266(8):4943-50.|
|Binding of benzoquinoid ansamycins to p100 correlates with their ability to deplete the erbB2 gene product p185.|
|Miller P, Schnur RC, Barbacci E, Moyer MP, Moyer JD.|
|Biochem Biophys Res Commun. 1994 Jun 30;201(3):1313-9.|
|Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation.|
|Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM.|
|Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8324-8.|
|Binding of p23 and hsp90 during assembly with the progesterone receptor.|
|Johnson JL, Toft DO.|
|Mol Endocrinol. 1995 Jun;9(6):670-8.|
|Antibiotics and prevention of microbial colonization of catheters.|
|Raad I, Darouiche R, Hachem R, Sacilowski M, Bodey GP.|
|Antimicrob Agents Chemother. 1995 Nov;39(11):2397-400.|
|Herbimycin A induces the 20 S proteasome- and ubiquitin-dependent degradation of receptor tyrosine kinases.|
|Sepp-Lorenzino L, Ma Z, Lebwohl DE, Vinitsky A, Rosen N.|
|J Biol Chem. 1995 Jul 14;270(28):16580-7.|
|Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent.|
|Supko JG, Hickman RL, Grever MR, Malspeis L.|
|Cancer Chemother Pharmacol. 1995;36(4):305-15.|
|Mutant conformation of p53 translated in vitro or in vivo requires functional HSP90.|
|Blagosklonny MV, Toretsky J, Bohen S, Neckers L.|
|Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8379-83.|
|The interaction of coumarin antibiotics with fragments of DNA gyrase B protein.|
|Gormley NA, Orphanides G, Meyer A, Cullis PM, Maxwell A.|
|Biochemistry. 1996 Apr 16;35(15):5083-92.|
|Depletion of p185erbB2, Raf-1 and mutant p53 proteins by geldanamycin derivatives correlates with antiproliferative activity.|
|An WG, Schnur RC, Neckers L, Blagosklonny MV.|
|Cancer Chemother Pharmacol. 1997;40(1):60-4.|
|Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent.|
|Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP.|
|Cell. 1997 Apr 18;89(2):239-50.|
|The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review.|
|Csermely P, Schnaider T, Soti C, Prohaszka Z, Nardai G.|
|Pharmacol Ther. 1998 Aug;79(2):129-68. (REVIEW)|
|A prospective crossover randomized trial of novobiocin and rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2.|
|Raad II, Hachem RY, Abi-Said D, Rolston KV, Whimbey E, Buzaid AC, Legha S.|
|Cancer. 1998 Jan 15;82(2):403-11.|
|The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin.|
|Schulte TW, Neckers LM.|
|Cancer Chemother Pharmacol. 1998;42(4):273-9.|
|Synthesis and evaluation of geldanamycin-estradiol hybrids.|
|Kuduk SD, Zheng FF, Sepp-Lorenzino L, Rosen N, Danishefsky SJ.|
|Bioorg Med Chem Lett. 1999 May 3;9(9):1233-8.|
|Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin.|
|Roe SM, Prodromou C, O'Brien R, Ladbury JE, Piper PW, Pearl LH.|
|J Med Chem. 1999 Jan 28;42(2):260-6.|
|Synthesis and evaluation of geldanamycin-testosterone hybrids.|
|Kuduk SD, Harris TC, Zheng FF, Sepp-Lorenzino L, Ouerfelli Q, Rosen N, Danishefsky SJ.|
|Bioorg Med Chem Lett. 2000 Jun 5;10(11):1303-6.|
|The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone.|
|Marcu MG, Chadli A, Bouhouche I, Catelli M, Neckers LM.|
|J Biol Chem. 2000a Nov 24;275(47):37181-6.|
|Novobiocin and related coumarins and depletion of heat shock protein 90-dependent signaling proteins.|
|Marcu MG, Schulte TW, Neckers L.|
|J Natl Cancer Inst. 2000b Feb 2;92(3):242-8.|
|Structure-activity studies of novobiocin analogs as modulators of the cytotoxicity of etoposide (VP-16).|
|Rappa G, Shyam K, Lorico A, Fodstad O, Sartorelli AC.|
|Oncol Res. 2000;12(3):113-9.|
|Modulation of Akt kinase activity by binding to Hsp90.|
|Sato S, Fujita N, Tsuruo T.|
|Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10832-7.|
|A novel mechanism for chaperone-mediated telomerase regulation during prostate cancer progression.|
|Akalin A, Elmore LW, Forsythe HL, Amaker BA, McCollum ED, Nelson PS, Ware JL, Holt SE.|
|Cancer Res. 2001 Jun 15;61(12):4791-6.|
|A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells.|
|Chiosis G, Timaul MN, Lucas B, Munster PN, Zheng FF, Sepp-Lorenzino L, Rosen N.|
|Chem Biol. 2001 Mar;8(3):289-99.|
|Stable association of hsp90 and p23, but Not hsp70, with active human telomerase.|
|Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE.|
|J Biol Chem. 2001 May 11;276(19):15571-4. Epub 2001 Mar 23.|
|Development of a purine-scaffold novel class of Hsp90 binders that inhibit the proliferation of cancer cells and induce the degradation of Her2 tyrosine kinase.|
|Chiosis G, Lucas B, Shtil A, Huezo H, Rosen N.|
|Bioorg Med Chem. 2002 Nov;10(11):3555-64.|
|Binding of ATP to heat shock protein 90: evidence for an ATP-binding site in the C-terminal domain.|
|Garnier C, Lafitte D, Tsvetkov PO, Barbier P, Leclerc-Devin J, Millot JM, Briand C, Makarov AA, Catelli MG, Peyrot V.|
|J Biol Chem. 2002 Apr 5;277(14):12208-14. Epub 2002 Jan 22.|
|The search for synonyms among streptomycetes by using SDS-PAGE of whole-cell proteins. Emendation of the species Streptomyces aurantiacus, Streptomyces cacaoi subsp. cacaoi, Streptomyces caeruleus and Streptomyces violaceus.|
|Lanoot B, Vancanneyt M, Cleenwerck I, Wang L, Li W, Liu Z, Swings J.|
|Int J Syst Evol Microbiol. 2002 May;52(Pt 3):823-9.|
|HSP90 as a new therapeutic target for cancer therapy: the story unfolds.|
|Maloney A, Workman P.|
|Expert Opin Biol Ther. 2002 Jan;2(1):3-24. (REVIEW)|
|Hsp90 inhibitors as novel cancer chemotherapeutic agents.|
|Trends Mol Med. 2002;8(4 Suppl):S55-61. (REVIEW)|
|Geldanamycine derivative and method of treating cancer using same.|
|Snader KM, Vishnuvajjala BR, Holling-Shead M, Sausville EA.|
|The United States of America, represented by the secretary, Department of health and human services. 2002 Oct. PCT. Int. Appl. WO 2002079167.|
|A Nucleotide-dependent molecular switch controls ATP binding at the C-terminal domain of Hsp90. N-terminal nucleotide binding unmasks a C-terminal binding pocket.|
|Soti C, Racz A, Csermely P.|
|J Biol Chem. 2002 Mar 1;277(9):7066-75. Epub 2001 Dec 19.|
|A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors.|
|Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, Burrows FJ.|
|Nature. 2003 Sep 25;425(6956):407-10.|
|Development of radicicol analogues.|
|Soga S, Shiotsu Y, Akinaga S, Sharma SV.|
|Curr Cancer Drug Targets. 2003 Oct;3(5):359-69. (REVIEW)|
|Hsp90: the vulnerable chaperone.|
|Chiosis G, Vilenchik M, Kim J, Solit D.|
|Drug Discov Today. 2004 Oct 15;9(20):881-8. (REVIEW)|
|The crystal structure of the carboxy-terminal dimerization domain of htpG, the Escherichia coli Hsp90, reveals a potential substrate binding site.|
|Harris SF, Shiau AK, Agard DA.|
|Structure. 2004 Jun;12(6):1087-97.|
|Hsp90: from structure to phenotype.|
|Jackson SE, Queitsch C, Toft D.|
|Nat Struct Mol Biol. 2004 Dec;11(12):1152-5.|
|High-throughput screening assay for inhibitors of heat-shock protein 90 ATPase activity.|
|Rowlands MG, Newbatt YM, Prodromou C, Pearl LH, Workman P, Aherne W.|
|Anal Biochem. 2004 Apr 15;327(2):176-83.|
|Hsp90 isoforms: functions, expression and clinical importance.|
|Sreedhar AS, Kalmar E, Csermely P, Shen YF.|
|FEBS Lett. 2004a Mar 26;562(1-3):11-5. (REVIEW)|
|Inhibition of Hsp90: a new strategy for inhibiting protein kinases.|
|Sreedhar AS, Soti C, Csermely P.|
|Biochim Biophys Acta. 2004b Mar 11;1697(1-2):233-42. (REVIEW)|
|Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90.|
|Vilenchik M, Solit D, Basso A, Huezo H, Lucas B, He H, Rosen N, Spampinato C, Modrich P, Chiosis G.|
|Chem Biol. 2004 Jun;11(6):787-97.|
|Altered states: selectively drugging the Hsp90 cancer chaperone.|
|Trends Mol Med. 2004 Feb;10(2):47-51. (REVIEW)|
|Novobiocin induces a distinct conformation of Hsp90 and alters Hsp90-cochaperone-client interactions.|
|Yun BG, Huang W, Leach N, Hartson SD, Matts RL.|
|Biochemistry. 2004 Jun 29;43(25):8217-29.|
|Targeting multiple signal transduction pathways through inhibition of Hsp90.|
|Zhang H, Burrows F.|
|J Mol Med. 2004 Aug;82(8):488-99. Epub 2004 May 27. (REVIEW)|
|Analogs of benzoquinone-containing ansamycins for the treatment of cancer.|
|Adams J, Gao Y, Georges Evangelinos AT, Grenier L, Pak RH, Porter JR, Wright JL.|
|Infinity Pharmaceuticals, INC. 2005 Jul. PCT. Int. Appl. WO 2005063714.|
|Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies.|
|Banerji U, O'Donnell A, Scurr M, Pacey S, Stapleton S, Asad Y, Simmons L, Maloney A, Raynaud F, Campbell M, Walton M, Lakhani S, Kaye S, Workman P, Judson I.|
|J Clin Oncol. 2005 Jun 20;23(18):4152-61.|
|The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors.|
|Cheung KM, Matthews TP, James K, Rowlands MG, Boxall KJ, Sharp SY, Maloney A, Roe SM, Prodromou C, Pearl LH, Aherne GW, McDonald E, Workman P.|
|Bioorg Med Chem Lett. 2005 Jul 15;15(14):3338-43.|
|Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design.|
|Dymock BW, Barril X, Brough PA, Cansfield JE, Massey A, McDonald E, Hubbard RE, Surgenor A, Roughley SD, Webb P, Workman P, Wright L, Drysdale MJ.|
|J Med Chem. 2005 Jun 30;48(13):4212-5.|
|Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles.|
|Kreusch A, Han S, Brinker A, Zhou V, Choi HS, He Y, Lesley SA, Caldwell J, Gu XJ.|
|Bioorg Med Chem Lett. 2005 Mar 1;15(5):1475-8.|
|Evaluation of 8-arylsulfanyl, 8-arylsulfoxyl, and 8-arylsulfonyl adenine derivatives as inhibitors of the heat shock protein 90.|
|Llauger L, He H, Kim J, Aguirre J, Rosen N, Peters U, Davies P, Chiosis G.|
|J Med Chem. 2005 Apr 21;48(8):2892-905.|
|Heat-shock protein 90 inhibitors as novel cancer chemotherapeutics - an update.|
|Neckers L, Neckers K.|
|Expert Opin Emerg Drugs. 2005 Feb;10(1):137-49. (REVIEW)|
|Hsp90 inhibitors identified from a library of novobiocin analogues.|
|Yu XM, Shen G, Neckers L, Blake H, Holzbeierlein J, Cronk B, Blagg BS.|
|J Am Chem Soc. 2005 Sep 21;127(37):12778-9.|
|Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex.|
|Ali MM, Roe SM, Vaughan CK, Meyer P, Panaretou B, Piper PW, Prodromou C, Pearl LH.|
|Nature. 2006 Apr 20;440(7087):1013-7.|
|Novobiocin analogues as anticancer agents.|
|Blagg BS, Neckers L, Yu XM.|
|University of Kansas/Department of health and human services. 2006 Mai. PCT. Int. Appl. WO 2006050501.|
|Novobiocin: redesigning a DNA gyrase inhibitor for selective inhibition of hsp90.|
|Burlison JA, Neckers L, Smith AB, Maxwell A, Blagg BS.|
|J Am Chem Soc. 2006 Dec 6;128(48):15529-36.|
|Targeting chaperones in transformed systems--a focus on Hsp90 and cancer.|
|Expert Opin Ther Targets. 2006 Feb;10(1):37-50.|
|Heat shock protein-90 inhibitors: a chronicle from geldanamycin to today's agents.|
|Chiosis G, Caldas Lopes E, Solit D.|
|Curr Opin Investig Drugs. 2006 Jun;7(6):534-41. (REVIEW)|
|Tumor selectivity of Hsp90 inhibitors: the explanation remains elusive.|
|Chiosis G, Neckers L.|
|ACS Chem Biol. 2006 Jun 20;1(5):279-84. (REVIEW)|
|The Hsp90 cochaperone p23 is essential for perinatal survival.|
|Grad I, McKee TA, Ludwig SM, Hoyle GW, Ruiz P, Wurst W, Floss T, Miller CA 3rd, Picard D.|
|Mol Cell Biol. 2006 Dec;26(23):8976-83. Epub 2006 Sep 25.|
|V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors.|
|Grbovic OM, Basso AD, Sawai A, Ye Q, Friedlander P, Solit D, Rosen N.|
|Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):57-62. Epub 2005 Dec 21.|
|Tetrahydroindolone and tetrahydroindazolone derivatives.|
|Huang KH, Eaves J, Veal J, Barta T, Geng L, Hinkley L, Hanson G.|
|Serrnex, Inc. 2006 Aug. PCT. Int. Appl. WO 2006091963.|
|Phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of intravenous alvespimycin (KOS-1022) in patients with refractory hematological malignancies.|
|Lancet J, Baer MR, Gojo I, Burton M, Quinn M, Tighe SM, Bhalla K, Kersey K, Wells S, Zhong Z, Sadler B, Albitar M, Johnson R, Hannah A.|
|Blood (ASH Annual Meeting Abstracts), 2006;108:Abstract 1961.|
|Dihydroquinone ansamycins: toward resolving the conflict between low in vitro affinity and high cellular potency of geldanamycin derivatives.|
|Maroney AC, Marugan JJ, Mezzasalma TM, Barnakov AN, Garrabrant TA, Weaner LE, Jones WJ, Barnakova LA, Koblish HK, Todd MJ, Masucci JA, Deckman IC, Galemmo RA Jr, Johnson DL.|
|Biochemistry. 2006 May 2;45(17):5678-85.|
|Using natural product inhibitors to validate Hsp90 as a molecular target in cancer.|
|Curr Top Med Chem. 2006;6(11):1163-71. (REVIEW)|
|Structure and mechanism of the Hsp90 molecular chaperone machinery.|
|Pearl LH, Prodromou C.|
|Annu Rev Biochem. 2006;75:271-94. (REVIEW)|
|Chaperoning steroid hormone action.|
|Trends Endocrinol Metab. 2006 Aug;17(6):229-35. Epub 2006 Jun 27. (REVIEW)|
|Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors.|
|Powers MV, Workman P.|
|Endocr Relat Cancer. 2006 Dec;13 Suppl 1:S125-35. (REVIEW)|
|Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol.|
|Proisy N, Sharp SY, Boxall K, Connelly S, Roe SM, Prodromou C, Slawin AM, Pearl LH, Workman P, Moody CJ.|
|Chem Biol. 2006 Nov;13(11):1203-15.|
|A phase II trial of 17-(Allylamino)-17-demethoxygeldanamycin in patients with papillary and clear cell renal cell carcinoma.|
|Ronnen EA, Kondagunta GV, Ishill N, Sweeney SM, Deluca JK, Schwartz L, Bacik J, Motzer RJ.|
|Invest New Drugs. 2006 Nov;24(6):543-6.|
|Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT.|
|Sain N, Krishnan B, Ormerod MG, De Rienzo A, Liu WM, Kaye SB, Workman P, Jackman AL.|
|Mol Cancer Ther. 2006 May;5(5):1197-208.|
|Inhibitors of the HSP90 molecular chaperone: current status.|
|Sharp S, Workman P.|
|Adv Cancer Res. 2006;95:323-48. (REVIEW)|
|Structural Analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements.|
|Shiau AK, Harris SF, Southworth DR, Agard DA.|
|Cell. 2006 Oct 20;127(2):329-40.|
|Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90.|
|Sydor JR, Normant E, Pien CS, Porter JR, Ge J, Grenier L, Pak RH, Ali JA, Dembski MS, Hudak J, Patterson J, Penders C, Pink M, Read MA, Sang J, Woodward C, Zhang Y, Grayzel DS, Wright J, Barrett JA, Palombella VJ, Adams J, Tong JK.|
|Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17408-13. Epub 2006 Nov 7.|
|Targeted therapy of multiple myeloma based upon tumor-microenvironmental interactions.|
|Exp Hematol. 2007 Apr;35(4 Suppl 1):155-62.|
|The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins.|
|Dickey CA, Kamal A, Lundgren K, Klosak N, Bailey RM, Dunmore J, Ash P, Shoraka S, Zlatkovic J, Eckman CB, Patterson C, Dickson DW, Nahman NS Jr, Hutton M, Burrows F, Petrucelli L.|
|J Clin Invest. 2007 Mar;117(3):648-58. Epub 2007 Feb 15.|
|Hsp90 Maintains the Stability and Function of the Tau Phosphorylating Kinase GSK3beta.|
|Dou F, Chang X, Ma D.|
|Int J Mol Sci. 2007;8:51-60.|
|The glucocorticoid responses are shaped by molecular chaperones.|
|Grad I, Picard D.|
|Mol Cell Endocrinol. 2007 Sep 15;275(1-2):2-12. Epub 2007 Jun 2.|
|Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity.|
|Kasibhatla SR, Hong K, Biamonte MA, Busch DJ, Karjian PL, Sensintaffar JL, Kamal A, Lough RE, Brekken J, Lundgren K, Grecko R, Timony GA, Ran Y, Mansfield R, Fritz LC, Ulm E, Burrows FJ, Boehm MF.|
|J Med Chem. 2007 Jun 14;50(12):2767-78. Epub 2007 May 8.|
|Crystal structure of 3-((2,2-dimethylchroman-6-yl)-carbonylamino)-7-hydroxy-8-methyl-2-oxo-2 H-chromen-4-yl toluene-4-sulfonate, C29H27NO8S.|
|Le Bras G, Bekaert A, Viossat B, Peyrat JF, Alami M, Brion JD, Lemoine P.|
|Z. Kristallogr. 2007a;222:1-2.|
|New novobiocin analogues as antiproliferative agents in breast cancer cells and potential inhibitors of heat shock protein 90.|
|Le Bras G, Radanyi C, Peyrat JF, Brion JD, Alami M, Marsaud V, Stella B, Renoir JM.|
|J Med Chem. 2007b Nov 29;50(24):6189-200. Epub 2007 Nov 3.|
|Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies.|
|Luo W, Dou F, Rodina A, Chip S, Kim J, Zhao Q, Moulick K, Aguirre J, Wu N, Greengard P, Chiosis G.|
|Proc Natl Acad Sci U S A. 2007 May 29;104(22):9511-6. Epub 2007 May 21.|
|From the bench to the bedside: emerging new treatments in multiple myeloma.|
|Mitsiades CS, Hayden PJ, Anderson KC, Richardson PG.|
|Best Pract Res Clin Haematol. 2007 Dec;20(4):797-816. (REVIEW)|
|Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study.|
|Modi S, Stopeck AT, Gordon MS, Mendelson D, Solit DB, Bagatell R, Ma W, Wheler J, Rosen N, Norton L, Cropp GF, Johnson RG, Hannah AL, Hudis CA.|
|J Clin Oncol. 2007 Dec 1;25(34):5410-7.|
|Conformational dynamics of the molecular chaperone Hsp90 in complexes with a co-chaperone and anticancer drugs.|
|Phillips JJ, Yao ZP, Zhang W, McLaughlin S, Laue ED, Robinson CV, Jackson SE.|
|J Mol Biol. 2007 Oct 5;372(5):1189-203. Epub 2007 Apr 27.|
|Inhibitors of the heat shock response: biology and pharmacology.|
|Powers MV, Workman P.|
|FEBS Lett. 2007 Jul 31;581(19):3758-69. Epub 2007 May 25.|
|In vitro biological characterization of a novel, synthetic diaryl pyrazole resorcinol class of heat shock protein 90 inhibitors.|
|Sharp SY, Boxall K, Rowlands M, Prodromou C, Roe SM, Maloney A, Powers M, Clarke PA, Box G, Sanderson S, Patterson L, Matthews TP, Cheung KM, Ball K, Hayes A, Raynaud F, Marais R, Pearl L, Eccles S, Aherne W, McDonald E, Workman P.|
|Cancer Res. 2007a Mar 1;67(5):2206-16.|
|Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues.|
|Sharp SY, Prodromou C, Boxall K, Powers MV, Holmes JL, Box G, Matthews TP, Cheung KM, Kalusa A, James K, Hayes A, Hardcastle A, Dymock B, Brough PA, Barril X, Cansfield JE, Wright L, Surgenor A, Foloppe N, Hubbard RE, Aherne W, Pearl L, Jones K, McDonald E, Raynaud F, Eccles S, Drysdale M, Workman P.|
|Mol Cancer Ther. 2007b Apr;6(4):1198-211.|
|Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.|
|Solit DB, Ivy SP, Kopil C, Sikorski R, Morris MJ, Slovin SF, Kelly WK, DeLaCruz A, Curley T, Heller G, Larson S, Schwartz L, Egorin MJ, Rosen N, Scher HI.|
|Clin Cancer Res. 2007 Mar 15;13(6):1775-82.|
|2-Desmethyl ansamycin compounds.|
|Tian ZQ, McDaniel R, Myles DC, Patel KG, Piagentini M, Wang Z.|
|Kosan Biosciences, Inc. 2007, US 7,241,754 B2.|
|4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer.|
|Brough PA, Aherne W, Barril X, Borgognoni J, Boxall K, Cansfield JE, Cheung KM, Collins I, Davies NG, Drysdale MJ, Dymock B, Eccles SA, Finch H, Fink A, Hayes A, Howes R, Hubbard RE, James K, Jordan AM, Lockie A, Martins V, Massey A, Matthews TP, McDonald E, Northfield CJ, Pearl LH, Prodromou C, Ray S, Raynaud FI, Roughley SD, Sharp SY, Surgenor A, Walmsley DL, Webb P, Wood M, Workman P, Wright L.|
|J Med Chem. 2008 Jan 24;51(2):196-218. Epub 2007 Nov 20.|
|Molecular imaging of the efficacy of heat shock protein 90 inhibitors in living subjects.|
|Chan CT, Paulmurugan R, Gheysens OS, Kim J, Chiosis G, Gambhir SS.|
|Cancer Res. 2008 Jan 1;68(1):216-26.|
|SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers.|
|Chandarlapaty S, Sawai A, Ye Q, Scott A, Silinski M, Huang K, Fadden P, Partdrige J, Hall S, Steed P, Norton L, Rosen N, Solit DB.|
|Clin Cancer Res. 2008 Jan 1;14(1):240-8.|
|NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis.|
|Eccles SA, Massey A, Raynaud FI, Sharp SY, Box G, Valenti M, Patterson L, de Haven Brandon A, Gowan S, Boxall F, Aherne W, Rowlands M, Hayes A, Martins V, Urban F, Boxall K, Prodromou C, Pearl L, James K, Matthews TP, Cheung KM, Kalusa A, Jones K, McDonald E, Barril X, Brough PA, Cansfield JE, Dymock B, Drysdale MJ, Finch H, Howes R, Hubbard RE, Surgenor A, Webb P, Wood M, Wright L, Workman P.|
|Cancer Res. 2008 Apr 15;68(8):2850-60.|
|BIIB021, an oral, synthetic non-ansamycin Hsp90 inhibitor: Phase I experience.|
|Elfiky A, Saif MW, Beeram M, O'Brien S, Lammanna N, Castro JE, Woodworth J, Perea R, Storgard C, Von Hoff DD.|
|J Clin Oncol. 2008;26:No 15S.|
|NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models.|
|Jensen MR, Schoepfer J, Radimerski T, Massey A, Guy CT, Brueggen J, Quadt C, Buckler A, Cozens R, Drysdale MJ, Garcia-Echeverria C, Chene P.|
|Breast Cancer Res. 2008;10(2):R33. Epub 2008 Apr 22.|
|The novel HSP90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors.|
|Lin TY, Bear M, Du Z, Foley KP, Ying W, Barsoum J, London C.|
|Exp Hematol. 2008 Oct;36(10):1266-77. Epub 2008 Jul 26.|
|Heat shock protein 90: translation from cancer to Alzheimer's disease treatment?|
|Luo W, Rodina A, Chiosis G.|
|BMC Neurosci. 2008 Dec 3;9 Suppl 2:S7. (REVIEW)|
|Cisplatin abrogates the geldanamycin-induced heat shock response.|
|McCollum AK, Lukasiewicz KB, Teneyck CJ, Lingle WL, Toft DO, Erlichman C.|
|Mol Cancer Ther. 2008 Oct;7(10):3256-64.|
|Recent advances in Hsp90 inhibitors as antitumor agents.|
|Messaoudi S, Peyrat JF, Brion JD, Alami M.|
|Anticancer Agents Med Chem. 2008 Oct;8(7):761-82. (REVIEW)|
|Synthesis and biological activity of simplified denoviose-coumarins related to novobiocin as potent inhibitors of heat-shock protein 90 (hsp90).|
|Radanyi C, Le Bras G, Messaoudi S, Bouclier C, Peyrat JF, Brion JD, Marsaud V, Renoir JM, Alami M.|
|Bioorg Med Chem Lett. 2008 Apr 1;18(7):2495-8. Epub 2008 Feb 14.|
|Geldanamycin compounds and method of use.|
|Santi DV, Tian ZQ, Liu Y, Wang Z.|
|Kosan Biosciences Incorporated (Hayward, CA, US), 7378407, 2008, http://www.freepatentsonline.com/7378407.html.|
|Development and application of Hsp90 inhibitors.|
|Solit DB, Chiosis G.|
|Drug Discov Today. 2008 Jan;13(1-2):38-43. Epub 2007 Nov 26. (REVIEW)|
|Targeting Hsp90: small-molecule inhibitors and their clinical development.|
|Taldone T, Gozman A, Maharaj R, Chiosis G.|
|Curr Opin Pharmacol. 2008 Aug;8(4):370-4. Epub 2008 Jul 31. (REVIEW)|
|The antiproliferative activity of the heat shock protein 90 inhibitor IPI-504 is not dependent on NAD(P)H:quinone oxidoreductase 1 activity in vivo.|
|Douglas M, Lim AR, Porter JR, West K, Pink MM, Ge J, Wylie AA, Tibbits TT, Biggs K, Curtis M, Palombella VJ, Adams J, Fritz CC, Normant E.|
|Mol Cancer Ther. 2009 Dec;8(12):3369-78.|
|Neuroprotective activity and evaluation of Hsp90 inhibitors in an immortalized neuronal cell line.|
|Lu Y, Ansar S, Michaelis ML, Blagg BS.|
|Bioorg Med Chem. 2009 Feb 15;17(4):1709-15. Epub 2008 Dec 25.|
|BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90.|
|Lundgren K, Zhang H, Brekken J, Huser N, Powell RE, Timple N, Busch DJ, Neely L, Sensintaffar JL, Yang YC, McKenzie A, Friedman J, Scannevin R, Kamal A, Hong K, Kasibhatla SR, Boehm MF, Burrows FJ.|
|Mol Cancer Ther. 2009 Apr;8(4):921-9.|
|The novel HSP90 inhibitor STA-1474 exhibits biologic activity against osteosarcoma cell lines.|
|McCleese JK, Bear MD, Fossey SL, Mihalek RM, Foley KP, Ying W, Barsoum J, London CA.|
|Int J Cancer. 2009 Dec 15;125(12):2792-801.|
|SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK.|
|Okawa Y, Hideshima T, Steed P, Vallet S, Hall S, Huang K, Rice J, Barabasz A, Foley B, Ikeda H, Raje N, Kiziltepe T, Yasui H, Enatsu S, Anderson KC.|
|Blood. 2009 Jan 22;113(4):846-55. Epub 2008 Oct 23.|
|KU135, a novel novobiocin-derived C-terminal inhibitor of the 90-kDa heat shock protein, exerts potent antiproliferative effects in human leukemic cells.|
|Shelton SN, Shawgo ME, Matthews SB, Lu Y, Donnelly AC, Szabla K, Tanol M, Vielhauer GA, Rajewski RA, Matts RL, Blagg BS, Robertson JD.|
|Mol Pharmacol. 2009 Dec;76(6):1314-22. Epub 2009 Sep 9.|
|Triazole compounds that modulate Hsp90 activity.|
|Ying W, Sun L, Koya K, Chimmanamada DU, Zhang S, Przewloka T, Li H.|
|Synta Pharmaceuticals Corp. 2009 Feb. PCT. Int. Appl. WO 2009023211.|
|Heat shock protein 90: inhibitors in clinical trials.|
|Biamonte MA, Van de Water R, Arndt JW, Scannevin RH, Perret D, Lee WC.|
|J Med Chem. 2010 Jan 14;53(1):3-17.|
|Written||2010-04||Jean François Peyrat, Samir Messaoudi, Jean Daniel Brion, Mouad Alami|
|Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry, F-92296, France|
|This paper should be referenced as such :|
|Peyrat, JF ; Messaoudi, S ; Brion, JD ; Alami, M|
|Inhibitors of the heat shock protein 90: from cancer clinical trials to neurodegenerative diseases|
|Atlas Genet Cytogenet Oncol Haematol. 2011;15(1):89-105.|
|Free journal version : [ pdf ] [ DOI ]|
|On line version : http://AtlasGeneticsOncology.org/Deep/HSP90inCancerTreatmentID20086.htm|
|© Atlas of Genetics and Cytogenetics in Oncology and Haematology||indexed on : Tue Sep 26 12:38:24 CEST 2017|
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