Design and synthesis of novel 1,2,4-triazolobenzene sulfonamide derivatives as selective CDK1 inhibitors with potent in vivo anticancer efficacy

Cyclin-dependent kinase 1 (CDK1) is a key regulator of cell cycle progression and a potential therapeutic target for invasive malignancies. However, developing selective CDK1 inhibitors with manageable toxicity remains a significant challenge. In this study, a novel series of 1,2,4-triazolobenzene sulfonamide derivatives were designed and synthesized based on the structure of JNJ7706621 and its derivative 3n, and subjected to comprehensive bioactivity evaluation and structure-activity relationship discussion. Among them, 11l emerged as a highly promising lead compound, exhibiting nanomolar inhibitory activity against CDK1 (IC₅₀ = 5.5 nM) with high selectivity over CDK2, Aurora A, and CDK4, showing selectivity indices of 4.7-, 14.1-, and 73.2-fold, respectively. In vitro, 11l exhibited broad antiproliferative activity, particularly against HCT116 colon Cancer cells. Unlike conventional kinase inhibitors that solely suppress catalytic activity, 11l induced G2/M phase arrest and downregulated CDK1, cyclin B1, and the replication initiation factor CDC45. Further investigation revealed that 11l induces severe DNA replication stress, subsequently activating the p53 signaling pathway to trigger Apoptosis. This mechanism was recapitulated in CDC45 knockdown models. In vivo efficacy evaluation demonstrated that 30 mg/kg 11l achieved a tumor growth inhibition (TGI) rate of 56.4%, without inducing significant body weight loss or observable organ toxicity. Collectively, these findings identify 11l as a safe CDK1 Inhibitor with a distinct mechanism of action, supporting its potential as a promising therapeutic strategy for Cancer treatment.

1,2,4-triazolobenzene sulfonamide; Antitumor; CDC45; CDK1 inhibitor; p53 signaling pathway.