Abstract 5789: Discovery of clinical candidate BMS-986158, an oral BET inhibitor, for the treatment of cancer
Authors: Gavai Ashvinikumar V. , Norris Derek , Tortolani David , O'Malley Daniel , Zhao Yufen , Quesnelle Claude , Gill Patrice , Vaccaro Wayne , Huynh Tram , Ahuja Vijay , Dodd Dharmpal , Mussari Christopher , Harikrishnan Lalgudi , Kamau Muthoni , Tokarski John S. , Sheriff Steven , Rampulla Richard , Wu Dauh-Rurng , Li Jianqing , Zhang Huiping , Li Peng , Sun Dawn , Yip Henry , Zhang Yingru , Mathur Arvind , Zhang Haiying , Huang Christine , Yang Zheng , Ranasinghe Asoka , D'Arienzo Celia , Su Ching , Everlof Gerry , Zhang Lisa , Raghavan Nirmala , Hunt John T. , Poss Michael , Vite Gregory D. , Westhouse Richard A. , Wee Susan 
Published: August 2018

Abstract
Background: The bromodomains and extra-terminal domain (BET) proteins are a family of 4 adapter proteins, BRD2, BRD3, BRD4, and BRDT, that bind to specific acetylated lysine residues on the histone tails of chromatin and recruit additional proteins to regulate gene transcription. The c-MYC oncogene, which is amplified and deregulated in 40% to 70% of all cancers, is directly regulated by BET proteins. Preclinical studies provide a strong rationale for pursuing transcriptional regulation via BET inhibition in cancer treatment (Lenhart, et al. Mol Cancer Ther. 2015;14:2167-2174; Filippakopoulos, et al. Nature. 2010;468:1067-1073). Here, we present results of crystal structure-guided structure-activity relationship (SAR) studies that resulted in the identification of BMS-986158, a highly potent BET inhibitor.
Methods: Using fluorescence resonance energy transfer (FRET), we screened a library of compounds and identified a carbazole series of BET inhibitors. Alkylation of the carbazole nitrogen resulted in a 10-fold boost in potency against BET. We then created a differently oriented carbazole series and, subsequently, a carboline series of compounds to improve potency and pharmaceutical properties. A thermal shift assay was used to evaluate selectivity for binding to the BET family of bromodomains.
Results: Crystal structure and subsequent SAR studies demonstrated that the isoxazole moiety formed critical interactions with the BET bromodomains. Lead compounds demonstrated potent binding to BRD4 and reduction in c-MYC expression and proliferation in cell lines such as KMS-11. Accessing a second lipophilic pocket in the BRD4 binding site increased potency significantly. Modification of the lead series from a carbazole carboxamide to a carboline resulted in significant improvement in pharmaceutical properties and led to the identification of BMS-986158, which demonstrated in vitro and in vivo potency against a variety of tumor types. In c-MYC-driven cancer cell lines, BMS-986158 caused dose-dependent downregulation of c-MYC expression and induced cancer cell death. BMS-986158 demonstrated &gt; 70% tumor growth inhibition at tolerated doses in patient-derived xenograft models (lung, colorectal, and triple-negative breast cancers). Antitumor activity in mice and pharmacokinetic properties in animal studies support oral dosing in humans.
Conclusions: Structure-based drug design led to the discovery of BMS-986158, a highly potent BET inhibitor. With promising antitumor activity in preclinical studies, BMS-986158 is currently being evaluated in a phase 1/2a clinical trial in patients with advanced cancers.
Citation Format: Ashvinikumar V. Gavai, Derek Norris, David Tortolani, Daniel O'Malley, Yufen Zhao, Claude Quesnelle, Patrice Gill, Wayne Vaccaro, Tram Huynh, Vijay Ahuja, Dharmpal Dodd, Christopher Mussari, Lalgudi Harikrishnan, Muthoni Kamau, John S. Tokarski, Steven Sheriff, Richard Rampulla, Dauh-Rurng Wu, Jianqing Li, Huiping Zhang, Peng Li, Dawn Sun, Henry Yip, Yingru Zhang, Arvind Mathur, Haiying Zhang, Christine Huang, Zheng Yang, Asoka Ranasinghe, Celia D'Arienzo, Ching Su, Gerry Everlof, Lisa Zhang, Nirmala Raghavan, John T. Hunt, Michael Poss, Gregory D. Vite, Richard A. Westhouse, Susan Wee. Discovery of clinical candidate BMS-986158, an oral BET inhibitor, for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5789.