Discovery of TAS-116 as a novel orally available HSP90 inhibitor

Abstract

The molecular chaperone heat shock protein 90 (HSP90) is a promising target for cancer therapy, as it assists in the stabilization of cancer-related proteins, promoting cancer cell growth and survival. A novel series of HSP90 inhibitors were discovered by structure-activity relationship (SAR)-based optimization of an initial hit compound 1 having a 4-(4-(quinolin-3-yl)-1H-indol-1-yl) benzamide structure. TAS-116 (9) is a selective inhibitor of HSP90α and HSP90β among the HSP90 family proteins and exhibits oral availability in mice. The X-ray co-crystal structure of TAS-116 analog 8 demonstrated a unique binding mode at the N-terminal ATP binding site. Oral administration of TAS-116 demonstrated potent antitumor effects in an NCI-H1975 xenograft mouse model without significant loss of body weight. In this study, we report on the process of compound optimization from the initial hit compound 1 to the discovery of TAS-116, X-ray co-crystal structure analysis of compound 8, and the results of in vivo efficacy study.