Abstract 2768: IDH1057, A novel, synthetic, small molecule inhibitor of heat shock protein 90(Hsp90)

Abstract

Abstract Backgroud: The molecular chaperone Heat shock protein 90(Hsp90) governs the stabilization and activity of an array of over 100 ‘client proteins’, many of which are key signaling molecules involved in cell proliferation, survival, and transformation. A significant number of these client proteins are oncogenic in nature, including the protein kinases Her2, C-Raf, B-Raf, and AKT. We report here that IDH1057 is structurally distinct from a geldanamycin derivative, tanespimycin(17-AAG) as a novel and potent small molecule Hsp90 inhibitor that binds to the NH2-terminal ATP-binding pocket of Hsp90. Results: IDH1057 exhibited superior binding affinity for the ATPase domain of Hsp90(IDH1057, human Hsp90α FP IC50<150 nM) compared to 17-AAG(IC50 =456.3 nM) in vitro. IDH1057 also markedly inhibited proliferation in a broad panel of human tumor cell lines(IC50α100 nM) and depleted Her2 in SKBR3 breast cancer cells(IC50<50 nM). 10 NSCLC cell lines were relatively sensitive to IDH1057, irrespective of EGFR, Her2 or KRAS mutational status. IDH1057 was also highly effective against cell lines that displayed resistance to erlotinib. IDH1057 efficiently inhibited cell proliferation in 8 breast cancer cell lines including triple-negative breast cancer(TNBC) cell lines such as BT-20, Hs578T and MDA-MB-231. Exposure to IDH1057 led to a rapid and dramatic degradation of key signaling molecules in BT474 cells. Based on these results, we examined in vivo anti-tumor activity of IDH1057 in BT474 breast cancer xenografts. Following once daily oral dosing of IDH1057 at 200mg/kg on a weekly 5-day-on and 2-day-off schedule for 4 weeks, this compound showed statistically significant tumor growth inhibition(TGI=84.5%) and was well-tolerated with no observable body weight loss. A2780 ovarian cancer xenografts in mice treated orally with IDH1057 also resulted in potent tumor growth inhibition. More importantly, IDH1057 displayed favorable oral PK profiles in mice. Additionally, we performed in vitro ADME assays to characterize a new series of small molecule inhibitors. IDH1057 exhibited high metabolic stability in liver microsomes from human, mouse and beagle(≥60%). Five human CYP isoforms were not significantly inhibited by IDH1057 at 10uM. IDH1057 had moderate permeability in MDCK permeability assay(Papp=4.7x10−6 cm/sec). Conclusion: Our results indicate that IDH1057 is a novel and fully synthetic Hsp90 inhibitor with strong anti-tumor activity in vitro and in vivo. IDH1057 is a promising and orally active drug candidate for cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2768. doi:1538-7445.AM2012-2768