2. Academic Validation
  3. Design of Selective PARP-1 Inhibitors and Antitumor Studies

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

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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