2. Academic Validation
  3. Design, synthesis and evaluation of novel cycloalkylthiophene-based aminopyrimidine derivatives as potent PLK1 inhibitors

Design, synthesis and evaluation of novel cycloalkylthiophene-based aminopyrimidine derivatives as potent PLK1 inhibitors

  • Bioorg Med Chem Lett. 2025 Aug 15:124:130260. doi: 10.1016/j.bmcl.2025.130260.
Meixue Ai 1,  Yukang Lin 2,  Xiaoyu Zhong 1,  Zhongkai Zou 2,  Pengcheng Diao 2,  Yanting Zhang 2,  Jingkao Chen 2,  Peiliang Zhao 3,  Zhibo Zhu 4
Affiliations

Affiliations

  • 1 Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine，Southern Medical University, Guangzhou 510315, PR China.
  • 2 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, PR China.
  • 3 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, PR China. Electronic address: plzhao@smu.edu.cn.
  • 4 Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine，Southern Medical University, Guangzhou 510315, PR China. Electronic address: zhuzb676@smu.edu.cn.
PMID: 40311783 DOI: 10.1016/j.bmcl.2025.130260
Abstract

PLK1 plays a pivotal role in cell-cycle regulation and has been well-characterized as a promising target for Cancer therapy. Here, we synthesized a series of fused-thiophene based aminopyrimidine derivatives, and discovered a novel and potent PLK1 Inhibitor compound 7n with an IC50 value of 38.5 nM. Analogue 7n exhibited remarkable antiproliferative efficacy toward HepG2, Huh7, H1299, and A549 cells, and hasn't any noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies indicated 7n arrested the cell cycle at the G2/M phase and induced Apoptosis in HepG2 cells with a concentration-dependent manner. Molecular docking presented that 7n could occupy well the ATP-binding site of PLK1 with a U-shaped conformation. Collectively, these results provide new insights into the further development of fused-thiophene based aminopyrimidines as PLK1 inhibitors.

Keywords

Aminopyrimidines; Antiproliferative activity; Fused-thiophenes; PLK1.

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