VER 155008

VER 155008 is a potent inhibitor of heat shock protein 70 (Hsp70) family of chaperones, which have been shown to contribute to cancer cell survival via anti-apoptotic functions, that inhibits Hsp70 (with the value of 50% inhibition concentration IC₅₀ of 0.5 μM) as well as heat shock cognate 71 kDa protein (Hsc70) and 78 kDa glucose-regulated protein (Grp78) but to a lesser extent. X-ray crystallography analysis reveals that VER 155008 binds to the ATPase pocket of Hsp70 leading to the inhibition of the intrinsic ATPase activity of Hsp70. Study results also have demonstrated that VER 155008 induces cell proliferation and apoptosis in human cancer cell lines.

Reference

Massey AJ, Williamson DS, Browne H, Murray JB, Dokurno P, Shaw T, Macias AT, Daniels Z, Geoffroy S, Dopson M, Lavan P, Matassova N, Francis GL, Graham CJ, Parsons R, Wang Y, Padfield A, Comer M, Drysdale MJ, Wood M. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol. 2010; 66(3): 535-545

VER-155008, a small molecule inhibitor of HSP70 with potent anti-cancer activity on lung cancer cell lines.[Pubmed:24676905]

Exp Biol Med (Maywood). 2014 May;239(5):638-45.

Lung cancer is the most common malignancy and exhibits significant morbidity and mortality worldwide. Among all lung cancer subtypes, non-small-cell lung cancer (NSCLC) accounts for the majority of all lung cancer cases. Although there have been intensive investigations on the underlying mechanism of NSCLC development and progression, the exact molecular basis is not well understood. Further insights on important molecular regulators of lung cancer are needed for development of novel therapeutics. The heat shock protein (HSP) family is a group of molecular chaperones that assist in protein folding, modification, and transportation. Different HSPs are essential for tumor cell survival by binding diverse client proteins and regulating homeostasis. In the current study, we sought to characterize HSP70 and HSP90 as potent regulators of NSCLC growth. Our results indicate that differential expression of HSP70 is associated with the malignant phenotype of NSCLC cell lines and plays an important regulatory role in NSCLC cell proliferation. Moreover, a specific inhibitor of HSP70, VER-155008 significantly inhibits NSCLC proliferation and cell cycle progression. We showed that this effect is largely abolished by HSP70 overexpression, indicating that the inhibitory effect of VER-155008 on cell growth is specifically through HSP70 inhibition. In addition, 17-AAD, an inhibitor of HSP90, exerts a potent synergistic effect on NSCLC proliferation with VER-155008. We also observed that inhibition of HSP70 by VER-155008 can sensitize A549 cells to ionizing radiation. These data provide proof-of-principle that VER-155008 can be a good candidate for NSCLC treatment and HSP machinery is a good target for developing NSCLC therapeutics.

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells.[Pubmed:20012863]

Cancer Chemother Pharmacol. 2010 Aug;66(3):535-45.

PURPOSE: The anti-apoptotic function of the 70 kDa family of heat shock proteins and their role in cancer is well documented. Dual targeting of Hsc70 and Hsp70 with siRNA induces proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition. METHODS: We have previously described the discovery and synthesis of novel adenosine-derived inhibitors of the 70 kDa family of heat shock proteins; the first inhibitors described to target the ATPase binding domain. The in vitro activity of VER-155008 was evaluated in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors. RESULTS: VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI(50)s in the range 5.3-14.4 microM, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 cells. VER-155008 potentiated the apoptotic potential of a small molecule Hsp90 inhibitor in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level. CONCLUSION: These data suggest that small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/Hsp70 inhibition remain to be determined.

Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design.[Pubmed:19256508]

J Med Chem. 2009 Mar 26;52(6):1510-3.

The design and synthesis of novel adenosine-derived inhibitors of HSP70, guided by modeling and X-ray crystallographic structures of these compounds in complex with HSC70/BAG-1, is described. Examples exhibited submicromolar affinity for HSP70, were highly selective over HSP90, and some displayed potency against HCT116 cells. Exposure of compound 12 to HCT116 cells caused significant reduction in cellular levels of Raf-1 and Her2 at concentrations similar to that which caused cell growth arrest.

VER-155008 is an inhibitor of Hsp70, with IC50s of 0.5 μM, 2.6 μM, and 2.6 μM for Hsp70, Hsc70 and Grp7, respectively, and with a Kd of 0.3 μM for Hsp70.

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