2. Academic Validation
  3. Discovery of Quinazoline-2,4(1 H,3 H)-dione Derivatives Containing a Piperizinone Moiety as Potent PARP-1/2 Inhibitors─Design, Synthesis, In Vivo Antitumor Activity, and X-ray Crystal Structure Analysis

Discovery of Quinazoline-2,4(1 H,3 H)-dione Derivatives Containing a Piperizinone Moiety as Potent PARP-1/2 Inhibitors─Design, Synthesis, In Vivo Antitumor Activity, and X-ray Crystal Structure Analysis

  • J Med Chem. 2023 Oct 26;66(20):14095-14115. doi: 10.1021/acs.jmedchem.3c01152.
Jie Zhou 1,  Tingting Du 2 3,  Xiaoyu Wang 1,  Haiping Yao 1,  Jialing Deng 2 3,  Yan Li 4,  Xiaoguang Chen 2 3,  Li Sheng 4,  Ming Ji 2 3,  Bailing Xu 1
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 4 Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 37843892 DOI: 10.1021/acs.jmedchem.3c01152
Abstract

PARP-1/2 inhibitors have become an important therapeutic strategy for the treatment of HR-deficient tumors. However, discovery of new inhibitors with an improved and distinct pharmacological file still need enormous explorations. Herein, a series of novel highly potent PARP-1/2 inhibitors bearing an N-substituted piperazinone moiety were achieved. In particular, Cpd36 was identified as a distinct PARP Inhibitor, showing remarkable enzymatic activity not only toward PARP-1 (IC50 = 0.94 nM) and PARP-2 (IC50 = 0.87 nM) but also toward PARP-7 (IC50 = 0.21 nM), as well as high selectivity over other PARP isoforms. Furthermore, Cpd36 was orally bioavailable and significantly repressed the tumor growth in both breast Cancer and prostate Cancer xenograft model. The crystal structures of Cpd36 within PARP-1 and PARP-2 together with the predicted binding mode within PARP-7 revealed its binding features and provided insightful information for further developing highly potent and selective PARP-1 and/or PARP-7 inhibitors.

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