Design of Selective PARP-1 Inhibitors and Antitumor Studies

  • J Med Chem. 2024 Jun 13;67(11):8877-8901. doi: 10.1021/acs.jmedchem.3c02460.
Yiting Zhang  1 ,  Xiangqian Li  1  2 ,  Fang Liu  1 ,  Xiaoyi Bai  1 ,  Xiaochun Liu  3 ,  Hao Sun  1 ,  Chenxia Gao  1 ,  Yuxi Lin  1 ,  Pan Xing  1 ,  Jiqiang Zhu  4 ,  Ruihua Liu  1 ,  Zemin Wang  1 ,  Jiajia Dai  5 ,  Dayong Shi  1  2  4
Affiliations
  • 1. State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.
  • 2. Laboratory of Marine Drugs and Biological Products, Pilot National Laboratory for Marine Science and Technology, Qingdao 266237, China.
  • 3. Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China.
  • 4. Shandong Linghai Biotechnology Co.Ltd., Jinan 250299, Shandong, P. R. China.
  • 5. Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, Shandong, China.
PMID: 38776379 DOI: 10.1021/acs.jmedchem.3c02460
Abstract

Designing selective PARP-1 inhibitors has become a new strategy for Anticancer drug development. By sequence comparison of PARP-1 and PARP-2, we identified a possible selective site (S site) consisting of several different amino acid residues of α-5 helix and D-loop. Targeting this S site, 140 compounds were designed, synthesized, and characterized for their Anticancer activities and mechanisms. Compound I16 showed the highest PARP-1 enzyme inhibitory activity (IC50 = 12.38 ± 1.33 nM) and optimal selectivity index over PARP-2 (SI = 155.74). Oral administration of I16 (25 mg/kg) showed high inhibition rates of Hela and SK-OV-3 tumor cell xenograft models, both of which were higher than those of the oral positive drug Olaparib (50 mg/kg). In addition, I16 has an excellent safety profile, without significant toxicity at high oral doses. These findings provide a novel design strategy and chemotype for the development of safe, efficient, and highly selective PARP-1 inhibitors.

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