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

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.