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

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

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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