Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300

  • J Med Chem. 2016 Dec 8;59(23):10549-10563. doi: 10.1021/acs.jmedchem.6b01022.
Terry D Crawford  1 ,  F Anthony Romero  1 ,  Kwong Wah Lai  2 ,  Vickie Tsui  1 ,  Alexander M Taylor  3 ,  Gladys de Leon Boenig  1 ,  Cameron L Noland  1 ,  Jeremy Murray  1 ,  Justin Ly  1 ,  Edna F Choo  1 ,  Thomas L Hunsaker  1 ,  Emily W Chan  1 ,  Mark Merchant  1 ,  Samir Kharbanda  1 ,  Karen E Gascoigne  1 ,  Susan Kaufman  1 ,  Maureen H Beresini  1 ,  Jiangpeng Liao  2 ,  Wenfeng Liu  2 ,  Kevin X Chen  2 ,  Zhongguo Chen  2 ,  Andrew R Conery  3 ,  Alexandre Côté  3 ,  Hariharan Jayaram  3 ,  Ying Jiang  2 ,  James R Kiefer  1 ,  Tracy Kleinheinz  1 ,  Yingjie Li  2 ,  Jonathan Maher  1 ,  Eneida Pardo  3 ,  Florence Poy  3 ,  Kerry L Spillane  3 ,  Fei Wang  2 ,  Jian Wang  2 ,  Xiaocang Wei  2 ,  Zhaowu Xu  2 ,  Zhongya Xu  2 ,  Ivana Yen  1 ,  Laura Zawadzke  3 ,  Xiaoyu Zhu  2 ,  Steven Bellon  3 ,  Richard Cummings  3 ,  Andrea G Cochran  1 ,  Brian K Albrecht  3 ,  Steven Magnuson  1
Affiliations
  • 1. Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
  • 2. Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
  • 3. Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
PMID: 27682507 DOI: 10.1021/acs.jmedchem.6b01022
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.

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