Abstract 3693: Preclinical antitumor activity of SST0116CL1, a novel heat shock protein 90 (HSP90) inhibitor
Authors: Vesci Loredana , Milazzo Ferdinando , Carollo Valeria , Pace Silvia , Giannini Giuseppe 
Published: May 2015

Abstract
Hsp90 is a component of a molecular chaperone complex, involved in the folding, maturation and stabilisation of key signaling molecules which control cell proliferation, survival and transformation. It works by a modulation of a set of cancer-associated proteins, collectively referred to as ‘‘clients’'. Inhibition of Hsp90 causes simultaneous destabilization and eventual degradation of client proteins that result in suppression of tumor growth, and a number of novel synthetic HSP90 inhibitors are currently under oncology clinical investigations for the treatment of a wide variety of tumor types. SST0116CL1 (property of sigma-tau Research Switzerland S.A.) is a potent, second generation, small-molecule HSP90 inhibitor, with a chemical structure (4-amino substituted resorcino-isoxazole) unrelated to the first generation ansamycin family of HSP90 inhibitors. SST0116CL1 binds to the ATP binding pocket of HSP90, and interferes with HSP90 chaperone function thus resulting in client protein degradation and tumor growth inhibition. In in vitro studies, SST0116CL1 was shown to inhibit recombinant HSP90α and to induce the degradation of the oncogenic Her2 tyrosine kinase in BT-474 human breast cancer cells. Moreover, it was able to induce the destabilization and depletion of different client proteins, often overexpressed and constitutively activated in numerous types of hematological or solid human tumors. These results correlated well with those obtained from the cell proliferation assay as well as with the HSP90 competitive binding assay, and clearly suggested that target modulation of HSP90 was achieved. In preclinical in vivo studies, in different solid and hematological tumor xenograft models, such as A431 epidermoid carcinoma with EGFR overexpression, GTL-16 gastric carcinoma with c-Met overexpression, MV4;11 B-myelomonocytic leukemia with flt3 mutation, A2780/Dx multidrug resistant ovarian carcinoma with P-glycoprotein overexpression, SST0116CL1 delivered intravenously or intraperitoneally revealed a potency at least comparable or higher than that found with the HSP90 inhibitor NVP-AUY922, under Phase II clinical trials investigation, or chemotherapeutic drugs currently used in cancer therapy. SST0116CL1 showed to be a manageable compound when given according to different schedules (qd5x/w; q4d/w; q2dx3/w), since it was well-tolerated and active to inhibit the tumor growth. A modulation of PD biomarkers in terms of down-regulation of EGFR, AKT and CDK4 was reached in tumor lesions of A431 tumor bearing mice treated with SST0116CL1 and a down-regulation of c-Met, AKT and CDK4 was observed in tumors collected from GTL-16 tumor bearing mice. PK parameters demonstrated a rapid clearance of SST0116CL1 from normal tissues and a blood compartment with prolonged retention in tumors. On the complex, these results strongly encourage the selection of SST0116CL1 as a promising candidate for clinical trial.
Citation Format: Loredana Vesci, Ferdinando Milazzo, Valeria Carollo, Silvia Pace, Giuseppe Giannini. Preclinical antitumor activity of SST0116CL1, a novel heat shock protein 90 (HSP90) inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3693. doi:10.1158/1538-7445.AM2014-3693