2. Academic Validation
  3. Discovery of 8-Methyl-pyrrolo[1,2- a]pyrazin-1(2 H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors

Discovery of 8-Methyl-pyrrolo[1,2- a]pyrazin-1(2 H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors

  • J Med Chem. 2020 Apr 23;63(8):3956-3975. doi: 10.1021/acs.jmedchem.9b01784.
Zizhou Li 1 2,  Senhao Xiao 2 3 4,  Yaxi Yang 1 2,  Chao Chen 1 2,  Tian Lu 2 3,  Zhifeng Chen 3,  Hualiang Jiang 3,  Shijie Chen 3,  Cheng Luo 2 3,  Bing Zhou 1 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
  • 3 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 4 School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China.
PMID: 32208600 DOI: 10.1021/acs.jmedchem.9b01784
Abstract

The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for Cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over Other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.

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