Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design
Ashvinikumar V. Gavai, Derek Norris, George V. Delucca, David R. Tortolani, John S. Tokarski, Dharmpal S. Dodd, Daniel O’Malley, Yufen Zhao, Claude Quesnelle, Patrice Gill, Wayne Vaccaro, Tram Huynh, Vijay T. Ahuja, Wen-Ching Han, Christopher P. Mussari, Lalgudi S. Harikrishnan, Muthoni G. Kamau, Michael A. Poss, S. Sheriff, Chunhong Yan, Frank Marsilio, Krista Menard, Mei-Li Wen, Richard Rampulla, Dauh‐Rurng Wu, Jianqing Li, Huiping Zhang, Peng Li, Dawn Sun, Henry Yip, Sarah C. Traeger, Yingru Zhang, Arvind Mathur, Haiying Zhang, Christine Huang, Zheng Yang, Asoka Ranasinghe, Gerry Everlof, Nirmala Raghavan, Ching Kim Tye, Susan Wee, John T. Hunt, Gregory D. Vite, Richard A. Westhouse, Francis Y. Lee
Abstract
Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure–activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.