2. Academic Validation
  3. Preclinical Efficacy of TSL2109 in Prostate Cancer Treatment and Overcoming Enzalutamide Resistance

Preclinical Efficacy of TSL2109 in Prostate Cancer Treatment and Overcoming Enzalutamide Resistance

  • J Med Chem. 2025 Dec 25;68(24):25783-25793. doi: 10.1021/acs.jmedchem.5c03245.
Kai Yuan 1 2 3,  Wanqi Wang 1 2 4,  Chen Tong 1 5,  Huanaoyu Yang 1 2,  Weijiao Chen 1 2,  Xiao-Yu Zhang 1 2 3,  Genbei Wang 4,  Guixia Li 4,  Yuanyuan Chen 1 2,  Xujie Zhuang 1 2,  Wenjian Min 1 2,  Haiping Hao 1 5 3,  Yibei Xiao 1 5 3,  Xiaohui Ma 4,  Peng Yang 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory of Targetome and innovative Drugs Medicines, China Pharmaceutical University, Nanjing 211198, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Institute of Innovative Drug, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Tasly Academy, Tasly Pharmaceutical Group Co., Ltd., Tianjin 300410, China.
  • 5 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
PMID: 41362128 DOI: 10.1021/acs.jmedchem.5c03245
Abstract

Prostate Cancer (PCa) is a highly prevalent and aggressive malignancy that poses a serious threat to men's health globally. Current treatments for PCa largely rely on hormone therapy; however, the development of drug resistance significantly diminishes its efficacy, highlighting the urgent need for novel therapeutic agents. Based on our prior work identifying dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) as a promising target in PCa, we developed a novel and potent DYRK2 Inhibitor TSL2109, and resolved its cocrystal structure with DYRK2. TSL2109 exhibited high kinase selectivity, favorable pharmacokinetic properties, and potent antitumor activity against PCa. Notably, it effectively suppressed tumor growth in enzalutamide-resistant 22Rv1 xenografts, patient-derived organoids, and patient-derived xenografts. Collectively, these results indicate that TSL2109 is a highly promising Anticancer agent with the potential to overcome therapy resistance, thereby addressing an unmet clinical need. Supported by these findings, TSL2109 has been approved for clinical trials in China.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-180574
    DYRK 抑制剂
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