Discovery and anti-tumor activity of 4-(benzylamino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2(1H)-one (CG13250), a potent, selective and orally bioavailable BET bromodomain inhibitor

Jay Chauhan; Makoto Yoshioka; Sarah Pogash; Jeffrey W Strovel; Steven Fletcher

doi:10.1016/j.bmcl.2023.129220

Discovery and anti-tumor activity of 4-(benzylamino)-6-(3,5-dimethylisoxazol-4-yl)quinolin-2(1H)-one (CG13250), a potent, selective and orally bioavailable BET bromodomain inhibitor

Bioorg Med Chem Lett. 2023 Apr 15:86:129220. doi: 10.1016/j.bmcl.2023.129220. Epub 2023 Mar 9.

Authors

Jay Chauhan¹, Makoto Yoshioka², Sarah Pogash¹, Jeffrey W Strovel², Steven Fletcher³

Affiliations

¹ Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA.
² ConverGene LLC, 4800 Montgomery Lane, c/o Dreyfuss 10th Floor, Bethesda, MD 20814, USA.
³ Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA; University of Maryland Greenebaum Cancer Center, Baltimore, MD 21201, USA. Electronic address: steven.fletcher@rx.umaryland.edu.

PMID: 36905966
DOI: 10.1016/j.bmcl.2023.129220

Abstract

The bromodomain and extra-terminal domain (BET) proteins are epigenetic readers involved in the regulation of gene transcription. Inhibitors of the BET proteins, in particular BRD4, have demonstrated anti-tumour activities and efficacies in clinical trials. Herein, we describe the discovery of potent and selective inhibitors of BRD4, and demonstrate that the lead compound CG13250 is orally bioavailable and efficacious in a mouse xenograft model of leukemia.

Keywords: BET; BRD4; Bromodomain; Cancer.

Publication types

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

MeSH terms

Animals
Cell Cycle Proteins
Disease Models, Animal
Humans
Leukemia* / drug therapy
Mice
Nuclear Proteins
Transcription Factors*

Substances

Transcription Factors
Nuclear Proteins
Cell Cycle Proteins
BRD4 protein, human