Discovery of 4-Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy

  • J Med Chem. 2022 May 12;65(9):6803-6825. doi: 10.1021/acs.jmedchem.2c00135.
Jifa Zhang  1 ,  Chengcan Yang  1 ,  Pan Tang  1 ,  Juncheng Chen  1 ,  Dan Zhang  1 ,  Yang Li  1 ,  Gaoxia Yang  1 ,  Yun Liu  1 ,  Yiwen Zhang  1 ,  Yuxi Wang  2 ,  Jie Liu  1 ,  Liang Ouyang  1
Affiliations
  • 1. State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Joint Research Institution of Altitude Health, West China Hospital of Sichuan University, Chengdu 610041, Sichuan,China.
  • 2. Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan,China.
PMID: 35442700 DOI: 10.1021/acs.jmedchem.2c00135
Abstract

The effective potency and resistance of poly(ADP-ribose) polymerase (PARP) inhibitors limit their application. Here, we exploit a new paradigm that mimics the effects of breast Cancer susceptibility genes (BRCA) mutations to trigger the possibility of synthetic lethality, based on the previous discovery of a potential synthetic lethality effect between bromodomain-containing protein 4 (BRD4) and PARP1. Consequently, the present study describes compound BP44 with high selectivity for BRD4 and PARP1. Fortunately, BP44 inhibits the homologous recombination in triple-negative breast Cancer (TNBC) and triggers synthetic lethality, thus leading to cell cycle arrest and DNA damage. In conclusion, we optimized the BRD4-PARP1 inhibitor based on previous studies, and we expect it to become a candidate drug for the treatment of TNBC in the future. This strategy aims to expand the use of PARPi in BRCA-competent TNBC, making an innovative approach to address unmet oncology needs.

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