Abstract 1729: Discovery of a synthetic small molecule inhibitor of HSP90 for cancer therapy

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA HSP90 is a major heat shock protein involved in the proper folding of its client proteins including many onco-proteins. HSP90 is elevated in tumor cells with a more active configuration, making it a potential target for cancer drug development. Utilizing structure-base design, we discovered a small molecule compound that inhibits HSP90 activity with an IC50 at low- nanomolar concentration. Cell proliferation was inhibited by this compound at a IC50 of single-digit nanomolar concentration across many different cancer cell lines. Mechanism of action studies demonstrated that this compound could induce HER-2 degradation in the breast cancer cell line BT-474 in vitro at concentrations between 100-300 nM. The compound showed an ideal pharmacological kinetic feature of less exposure and fast clearance in rat retina after intravenous administration, thus reducing the possibility of ocular toxicity as demonstrated by some other earlier HSP90 inhibitors. The compound also caused tumor growth inhibition in the xenograft tumor models, correlating with its target inhibition activity in these tumors. These data supports further development of this compound as a cancer therapeutic agent. Citation Format: Rudi Bao, Zhongzong Pan, Zhiming Zhao, Hongping Yu, Yaochang Xu. Discovery of a synthetic small molecule inhibitor of HSP90 for cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1729. doi:10.1158/1538-7445.AM2015-1729