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

  • J Med Chem. 2021 Nov 25;64(22):16711-16730. doi: 10.1021/acs.jmedchem.1c01522.
Jie Zhou 1,  Ming Ji 2 3,  Xiaoyu Wang 1,  Hailong Zhao 1,  Ran Cao 1,  Jing Jin 2 3,  Yan Li 4,  Xianhong Chen 4 5,  Li Sheng 4,  Xiaoguang Chen 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.
  • 5 Beijing Collab Pharma Co., Ltd, Beijing 102600, China.
PMID: 34748333 DOI: 10.1021/acs.jmedchem.1c01522
Abstract

Inhibiting PARP-1/2 offered an important arsenal for Cancer treatments via interfering with DNA repair of Cancer cells. Novel PARP-1/2 inhibitors were designed by capitalizing on methyl- or ethyl-substituted piperizine ring to capture the characteristics of adenine-ribose binding site (AD site), and their unique binding features were revealed by the cocrystal structures of compounds 4 and 6 in PARP-1. The investigation on structure-activity relationship resulted in compounds 24 and 32 with high enzymatic potency, binding selectivity, and significantly longer residence time for PARP-1 over PARP-2 (compound 24, PARP-1: IC50 = 0.51 nM, PARP-2: IC50 = 23.11 nM; compound 32, PARP-1: IC50 = 1.31 nM, PARP-2: IC50 = 15.63 nM). Furthermore, compound 24 was determined to be an attractive candidate molecule, which possessed an acceptable pharmacokinetic profile and produced remarkable antitumor activity in both breast Cancer xenograft model and glioblastoma orthotopic model in mice, either alone or in combination treatment.

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