Abstract 3896: Novel in vivo pan-Hsp90 family protein inhibitor, Panvotinib-401, showed potent anticancer activities without HSF1 activation

Abstract

Abstract Hsp90 family proteins are implicated in tumorigenesis and many inhibitors have been developed as cancer therapeutics. The inhibitors showed potent inhibitory activities against purified Hsp90 family proteins, Grp94 and TRAP1, as well as Hsp90 in vitro. The mitochondrial TRAP1, however, is not inactivated in vivo due to insufficient drug accumulation in the mitochondria. Here, we showed that simultaneous inactivation of Hsp90 family proteins in different compartments can augment anticancer activity of the Hsp90 inhibitors. When simultaneously inhibited, cytoplasmic calcium elevation and activation of calcineurin inhibited HSF1 triggering heat shock responses such as cytoprotective Hsp70 induction. To improve anticancer efficacy of Hsp90 inhibitors, we developed a small molecule (∼380 Da) mitochondrial inner membrane-permeable Hsp90 inhibitor, and named it as Panvotinib-401, briefly Pan-401. Pan-401 showed much improved cancer-selective cytotoxic activity compared with Hsp90 inhibitors or mitochondria-targeted (accumulating) inhibitor, gamitrinib. Collectively, with improved subcellular distribution, cancer-specific cytotoxic activity of Hsp90 inhibitors can be further enhanced. Citation Format: Byoung Heon Kang. Novel in vivo pan-Hsp90 family protein inhibitor, Panvotinib-401, showed potent anticancer activities without HSF1 activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3896.