| Literature DB >> 27682507 |
Terry D Crawford1, F Anthony Romero1, Kwong Wah Lai2, Vickie Tsui1, Alexander M Taylor3, Gladys de Leon Boenig1, Cameron L Noland1, Jeremy Murray1, Justin Ly1, Edna F Choo1, Thomas L Hunsaker1, Emily W Chan1, Mark Merchant1, Samir Kharbanda1, Karen E Gascoigne1, Susan Kaufman1, Maureen H Beresini1, Jiangpeng Liao2, Wenfeng Liu2, Kevin X Chen2, Zhongguo Chen2, Andrew R Conery3, Alexandre Côté3, Hariharan Jayaram3, Ying Jiang2, James R Kiefer1, Tracy Kleinheinz1, Yingjie Li2, Jonathan Maher1, Eneida Pardo3, Florence Poy3, Kerry L Spillane3, Fei Wang2, Jian Wang2, Xiaocang Wei2, Zhaowu Xu2, Zhongya Xu2, Ivana Yen1, Laura Zawadzke3, Xiaoyu Zhu2, Steven Bellon3, Richard Cummings3, Andrea G Cochran1, Brian K Albrecht3, Steven Magnuson1.
Abstract
The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC50 = 0.02 μM, BRET IC50 = 0.41 μM, BRD4(1) IC50 = 13 μM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.Entities:
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Year: 2016 PMID： 27682507 DOI： 10.1021/acs.jmedchem.6b01022
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446