1. Academic Validation
  2. Design, synthesis, and biological evaluation of novel N-(1 H-indazol-6-yl)benzenesulfonamide derivatives as potent PLK4 inhibitors

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

  • RSC Med Chem. 2025 May 13. doi: 10.1039/d5md00251f.
Pengkun Sun 1 Cunzheng Fan 1 Nian Liu 1 Minghui Tong 2 Xuan Shi 2 Han Wang 2 Shuyi Mu 1 Ningyuan Hu 1 Yixiang Sun 1 Haoyu Zhang 1 Zixuan Gao 1 Dongmei Zhao 1 Maosheng Cheng 1
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District Shenyang 110016 PR China medchemzhao@163.com.
  • 2 3D BioOptima 1338 Wuzhong Avenue Suzhou 215104 China.
Abstract

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 TRIM37 levels. Consequently, the development of safe, efficient, and highly selective PLK4 inhibitors is of considerable importance. This study examined existing PLK4 inhibitors, chose N-(1H-indazol-6-yl)benzenesulfonamide as the core structure, and synthesized a series of extremely effective PLK4 inhibitors by structural simplification and fragment growth methodologies. In vitro 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 (T 1/2 = 51.0 min). In the pharmacokinetic study, compound K22 exhibited a good area under the curve (AUC0-t = 447 ± 47.6 ng h mL-1) and acceptable half-life (T 1/2 = 1.07 ± 0.111 h). In summary, compound K22 has further research value as a PLK4 Inhibitor.

Figures
Products