2. Academic Validation
  3. Fluorocyclopropyl-Containing Tacrine Derivatives as Potent and Selective Dual CDK2/CDK9 Inhibitors for the Treatment of Colorectal Cancer

Fluorocyclopropyl-Containing Tacrine Derivatives as Potent and Selective Dual CDK2/CDK9 Inhibitors for the Treatment of Colorectal Cancer

  • J Med Chem. 2025 Nov 27;68(22):24326-24357. doi: 10.1021/acs.jmedchem.5c02328.
Limeng Wu 1 2,  Wenjie Liu 3,  Xinyue Ning 4,  Xinyu Li 2,  Zhiya Wang 2,  Zhenshu Li 2,  Yiming Qi 2,  Jiao Xiao 1,  Xiangbo Xu 4,  Xudong Gao 2,  Xinhua Liu 5,  Yingshi Zhang 4,  Zihua Xu 2,  Wenwu Liu 6,  Yonghong Liu 1 7,  Qingchun Zhao 1 2
Affiliations

Affiliations

  • 1 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
  • 2 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, P. R. China.
  • 3 College of Life and Health Sciences, Northeastern University, Shenyang 110819, P. R. China.
  • 4 Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
  • 5 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, P. R China.
  • 6 Department of Pharmacy, Peking University First Hospital, Beijing 100034, P. R. China.
  • 7 CAS Key Laboratory of Tropical Marine Bio-resources and Ecology/Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, P. R. China.
PMID: 41239996 DOI: 10.1021/acs.jmedchem.5c02328
Abstract

CDK2 and CDK9 play critical roles in cell cycle progression and transcriptional regulation, respectively. And CDK2/9 are highly expressed in colorectal Cancer (CRC), which dysregulation contributes significantly to CRC pathogenesis. Through structure-based drug design strategy we have identified ZLMT-72, a fluorocyclopropyl-containing tacrine derivative as a dual CDK2/9 inhibitor. Biological assay results indicated that ZLMT-72 exhibited potent inhibitory activity against both CDK2 (IC50 = 0.741 nM) and CDK9 (IC50 = 1.03 nM), demonstrating strong antiproliferative effects in the CRC cell line HCT116 (GI50 < 0.1 nM). Kinase profiling and cholinesterase inhibition assays confirmed a primary and potent inhibitory activity of ZLMT-72 against CDK2/9. Importantly, ZLMT-72 (10 mg/kg) displayed robust antitumor efficacy in both subcutaneous (TGI = 50.6%) and orthotopic (TGI = 84.3%) xenograft tumor models of HCT116, alongside favorable pharmacokinetic properties and a promising safety profile. Collectively, ZLMT-72, as a potent dual CDK2/9 inhibitor, holds substantial therapeutic potential for CRC treatment.

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