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

Zizhou Li; Senhao Xiao; Yaxi Yang; Chao Chen; Tian Lu; Zhifeng Chen; Hualiang Jiang; Shijie Chen; Cheng Luo; Bing Zhou

doi:10.1021/acs.jmedchem.9b01784

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. Epub 2020 Apr 7.

Authors

Zizhou Li^{1

2}, Senhao Xiao^{2

3

4}, Yaxi Yang^{1

2}, Chao Chen^{1

2}, Tian Lu^{2

3}, Zhifeng Chen³, Hualiang Jiang³, Shijie Chen³, Cheng Luo^{2

3}, Bing Zhou^{1

2}

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetanilides / chemistry*
Acetanilides / pharmacology*
Animals
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / metabolism
Dogs
Dose-Response Relationship, Drug
Drug Discovery / methods*
E1A-Associated p300 Protein / antagonists & inhibitors
E1A-Associated p300 Protein / metabolism
Haplorhini
Heterocyclic Compounds, 3-Ring / chemistry*
Heterocyclic Compounds, 3-Ring / pharmacology*
Humans
Mice
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Protein Domains / drug effects
Protein Domains / physiology
Protein Structure, Secondary
Pyridones / chemistry*
Pyridones / pharmacology*
Rats
Structure-Activity Relationship
Sulfonamides / chemistry*
Sulfonamides / pharmacology*
Transcription Factors / antagonists & inhibitors*
Transcription Factors / metabolism

Substances

Acetanilides
BRD4 protein, human
Cell Cycle Proteins
Heterocyclic Compounds, 3-Ring
OTX015
Pyridones
Sulfonamides
Transcription Factors
E1A-Associated p300 Protein
EP300 protein, human
mivebresib