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
  • 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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