2. Academic Validation
  3. Discovery of 2-(Pyrazol-4-yl)-quinazolin-4(3 H)-one Derivatives as Subnanomolar BRD4 BD2 Inhibitors with High Selectivity via a Bioisosterism Approach

Discovery of 2-(Pyrazol-4-yl)-quinazolin-4(3 H)-one Derivatives as Subnanomolar BRD4 BD2 Inhibitors with High Selectivity via a Bioisosterism Approach

  • J Med Chem. 2025 Sep 11;68(17):18314-18334. doi: 10.1021/acs.jmedchem.5c00924.
Shuxia Chen 1 2,  Jichen Yang 1 2,  Qiong Wu 3,  Jiaqi Zhou 1 2,  Hui Shen 4,  Xiangyu Wang 1 2,  Yong Xu 4,  Pingyuan Wang 1 2,  Chang-Yun Wang 1 2,  Yansheng Ye 3,  Zhiqing Liu 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China.
  • 2 Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China.
  • 3 State Key Laboratory of Magnetic Resonance Spectroscopy and Imaging, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, China.
  • 4 China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
PMID: 40892008 DOI: 10.1021/acs.jmedchem.5c00924
Abstract

BRD4, a bromodomain-containing protein, has emerged as an attractive therapeutic target for various diseases. Selective inhibition of the bromodomain is gaining traction as a promising strategy for targeted drug discovery. Based on bioisosterism-guided optimization of RVX-OH (8), a pan-BET inhibitor, we designed and synthesized a series of novel quinazolin-4(3H)-one derivatives as potent BRD4 inhibitors. Among them, 2-(1H-pyrazol-4-yl)quinazolin-4(3H)-one B6 exhibited subnanomolar BRD4 BD2 inhibitory activity with an IC50 value of 0.41 nM and a remarkably 39,683-fold selectivity over BRD4 BD1. 2D 1H-15N TROSY spectra distinctly demonstrated the high-affinity binding of B6 to BRD4 BD2. Furthermore, B6 obviously inhibited the lipopolysaccharide (LPS)-induced expression of interleukin (IL)-6. This potent and selective inhibitor B6 with cellular activity will further add to the understanding of individual bromodomains of BRD4 in epigenetic regulation and promote the discovery of novel lead compounds for the treatment of inflammatory diseases.

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