2. Academic Validation
  3. GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)

GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)

  • J Med Chem. 2017 Nov 22;60(22):9162-9183. doi: 10.1021/acs.jmedchem.7b00796.
F Anthony Romero 1,  Jeremy Murray 1,  Kwong Wah Lai 2,  Vickie Tsui 1,  Brian K Albrecht 3,  Le An 1,  Maureen H Beresini 1,  Gladys de Leon Boenig 1,  Sarah M Bronner 1,  Emily W Chan 1,  Kevin X Chen 2,  Zhongguo Chen 2,  Edna F Choo 1,  Kyle Clagg 1,  Kevin Clark 1,  Terry D Crawford 1,  Patrick Cyr 1,  Denise de Almeida Nagata 1,  Karen E Gascoigne 1,  Jane L Grogan 1,  Georgia Hatzivassiliou 1,  Wei Huang 2,  Thomas L Hunsaker 1,  Susan Kaufman 1,  Stefan G Koenig 1,  Ruina Li 1,  Yingjie Li 2,  Xiaorong Liang 1,  Jiangpeng Liao 2,  Wenfeng Liu 2,  Justin Ly 1,  Jonathan Maher 1,  Colin Masui 1,  Mark Merchant 1,  Yingqing Ran 1,  Alexander M Taylor 3,  John Wai 2,  Fei Wang 2,  Xiaocang Wei 2,  Dong Yu 2,  Bing-Yan Zhu 1,  Xiaoyu Zhu 2,  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: 28892380 DOI: 10.1021/acs.jmedchem.7b00796
Abstract

Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC50 = 0.94 nM, BRET IC50 = 6.2 nM; BRD4(1) IC50 = 5100 nΜ) that maintained good in vivo PK properties in multiple species. Compound 19 displays antitumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner.

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