2. Academic Validation
  3. Discovery of High-Affinity Inhibitors of the BPTF Bromodomain

Discovery of High-Affinity Inhibitors of the BPTF Bromodomain

  • J Med Chem. 2021 Aug 26;64(16):12075-12088. doi: 10.1021/acs.jmedchem.1c00721.
Tian Lu 1 2 3,  Haibo Lu 4 5,  Zhe Duan 5 6,  Jun Wang 5,  Jie Han 5,  Senhao Xiao 5,  HuanHuan Chen 7,  Hao Jiang 5,  Yu Chen 5,  Feng Yang 5,  Qi Li 5,  Dongying Chen 7,  Jin Lin 1,  Bo Li 5,  Hualiang Jiang 5,  Kaixian Chen 3 5,  Wenchao Lu 8,  Hua Lin 5 9,  Cheng Luo 1 3 4 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
  • 2 Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550025, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China.
  • 4 School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
  • 5 The Chemical Biology Center, Drug Design and Discovery Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 6 School of Pharmacy, Nanchang University, Nanchang 330006, China.
  • 7 Laboratory of Pharmaceutical Analysis, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China.
  • 8 Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States.
  • 9 Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou 350117, China.
PMID: 34375106 DOI: 10.1021/acs.jmedchem.1c00721
Abstract

The dysfunctional bromodomain PHD finger transcription factor (BPTF) exerts a pivotal influence in the occurrence and development of many human diseases, particularly cancers. Herein, through the structural decomposition of the reported BPTF inhibitor TP-238, the effective structural fragments were synthetically modified to obtain our lead compound DC-BPi-03. DC-BPi-03 was identified as a novel BPTF-BRD inhibitor with a moderate potency (IC50 = 698.3 ± 21.0 nM). A structure-guided structure-activity relationship exploration gave rise to two BPTF inhibitors with much higher affinities, DC-BPi-07 and DC-BPi-11. Notably, DC-BPi-07 and DC-BPi-11 show selectivities 100-fold higher than those of other BRD targets. The cocrystal structures of BPTF in complex with DC-BPi-07 and DC-BPi-11 demonstrate the rationale of chemical efforts from the atomic level. Further study showed that DC-BPi-11 significantly inhibited leukemia cell proliferation.

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