Design, synthesis, and biological evaluation of novel <i>N</i>-(1<i>H</i>-indazol-6-yl)benzenesulfonamide derivatives as potent PLK4 inhibitors

PLK4 is a serine/threonine protein kinase situated at the centrosome, acting as a crucial regulatory element in the regulation of cell mitosis and significantly contributing to the preservation of genomic integrity. The overexpression of PLK4 is intricately linked to the onset and progression of several cancers, influencing a range of actions in tumor cells, such as proliferation, differentiation, migration, and invasion. PLK4 has been identified as a target for the therapy of several malignancies, especially breast cancer characterized by elevated <i>TRIM37</i> levels. Consequently, the development of safe, efficient, and highly selective PLK4 inhibitors is of considerable importance. This study examined existing PLK4 inhibitors, chose <i>N</i>-(1<i>H</i>-indazol-6-yl)benzenesulfonamide as the core structure, and synthesized a series of extremely effective PLK4 inhibitors by structural simplification and fragment growth methodologies. <i>In vitro</i> enzyme activity studies demonstrated that compound K22 has significant PLK4 inhibitory activity (IC₅₀ = 0.1 nM). K22 demonstrated significant anti-proliferative efficacy against MCF-7 breast cancer cells at the cellular level (IC₅₀ = 1.3 μM). Moreover, PLK4 inhibitor K22 showed acceptable human liver microsome stability (<i>T</i> _1/2 = 51.0 min). In the pharmacokinetic study, compound K22 exhibited a good area under the curve (AUC_0-<i>t</i> = 447 ± 47.6 ng h mL^-1) and acceptable half-life (<i>T</i> _1/2 = 1.07 ± 0.111 h). In summary, compound K22 has further research value as a PLK4 inhibitor.