Advanced Design, Synthesis, and Evaluation of Highly Selective Wee1 Inhibitors: Enhancing Pharmacokinetics and Antitumor Efficacy

  • J Med Chem. 2024 Jun 27;67(12):9927-9949. doi: 10.1021/acs.jmedchem.3c02434.
Yong Wang  1 ,  Chunyue Xu  1 ,  Yiqing Jiang  1 ,  Zhenlin Tu  1 ,  Jingxue Yan  1 ,  Leyi Guo  1 ,  Chao Dong  1 ,  Jiaqi Liu  1 ,  Xiulong Yang  1 ,  Ziyi Wang  2 ,  Tao Lu  1  3 ,  Jie Feng  1 ,  Yadong Chen  1  3
Affiliations
  • 1. School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P.R. China.
  • 2. Schcool of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P.R. China.
  • 3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P.R. China.
PMID: 38847373 DOI: 10.1021/acs.jmedchem.3c02434
Abstract

Wee1 is a kinase that regulates cell cycle arrest in response to DNA damage. Wee1 inhibition is a potential strategy to suppress the growth of tumors with defective p53 or DNA repair pathways. However, the development of Wee1 inhibitors faces some challenges. AZD1775, the first-in-class Wee1 Inhibitor, has poor kinase selectivity and dose-limiting toxicity. Here, we report the discovery of 12h, a highly selective and potent Wee1 Inhibitor with a favorable pharmacokinetic profile. 12h showed strong antiproliferative effects against Lovo cells, a colorectal Cancer cell line, both in vitro and in vivo. Moreover, 12h showed a clean kinase profile and effectively induced cell Apoptosis. Our results suggest that 12h is a promising drug candidate for further development as a novel Anticancer agent.

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