2. Academic Validation
  3. Advanced Design, Synthesis, and Evaluation of Highly Selective Wee1 Inhibitors: Enhancing Pharmacokinetics and Antitumor Efficacy

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

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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