| Literature DB >> 34543572 |
Ashvinikumar V Gavai1, Derek Norris1, George Delucca1, David Tortolani1, John S Tokarski1, Dharmpal Dodd1, Daniel O'Malley1, Yufen Zhao1, Claude Quesnelle1, Patrice Gill1, Wayne Vaccaro1, Tram Huynh1, Vijay Ahuja1, Wen-Ching Han1, Christopher Mussari1, Lalgudi Harikrishnan1, Muthoni Kamau1, Michael Poss1, Steven Sheriff1, Chunhong Yan1, Frank Marsilio1, Krista Menard1, Mei-Li Wen1, Richard Rampulla1, Dauh-Rurng Wu1, Jianqing Li1, Huiping Zhang1, Peng Li1, Dawn Sun1, Henry Yip1, Sarah C Traeger1, Yingru Zhang1, Arvind Mathur1, Haiying Zhang1, Christine Huang1, Zheng Yang1, Asoka Ranasinghe1, Gerry Everlof1, Nirmala Raghavan1, Ching Kim Tye1, Susan Wee1, John T Hunt1, Gregory Vite1, Richard Westhouse1, Francis Y Lee1.
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.Entities:
Mesh：
Substances：
Year: 2021 PMID： 34543572 DOI： 10.1021/acs.jmedchem.1c00625
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446