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Published on: March 6, 2018
Preclinical Efficacy of TSL2109 in Prostate Cancer Treatment and Overcoming Enzalutamide Resistance
Kai Yuan1,2,3, Wanqi Wang1,2,4, Chen Tong1,5
1State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory of Targetome and innovative Drugs Medicines, China Pharmaceutical University, Nanjing 211198, China.
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.
Insights
A new drug, TSL2109, shows promise in treating prostate cancer (PCa) by targeting DYRK2. This potent inhibitor effectively combats drug-resistant PCa, offering hope for improved patient outcomes.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Prostate cancer (PCa) is a prevalent malignancy with limited treatment options due to drug resistance.
- Current hormone therapies for PCa often face efficacy challenges due to acquired resistance.
- Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) has been identified as a potential therapeutic target in PCa.
Purpose of the Study:
- To develop and characterize a novel DYRK2 inhibitor for prostate cancer treatment.
- To evaluate the efficacy of the DYRK2 inhibitor TSL2109 against drug-resistant PCa models.
- To assess the potential of TSL2109 to overcome therapeutic resistance in prostate cancer.
Main Methods:
- Development of a novel DYRK2 inhibitor, TSL2109.
- Cocrystallization of TSL2109 with DYRK2 to determine its structure.
- In vitro and in vivo evaluation of TSL2109's antitumor activity in PCa models, including resistant xenografts and organoids.
- Assessment of TSL2109's kinase selectivity and pharmacokinetic properties.
Main Results:
- TSL2109 demonstrated high kinase selectivity and favorable pharmacokinetic properties.
- The compound exhibited potent antitumor activity against various PCa models.
- TSL2109 effectively suppressed tumor growth in enzalutamide-resistant 22Rv1 xenografts, patient-derived organoids, and patient-derived xenografts.
- The cocrystal structure of TSL2109 with DYRK2 was resolved.
Conclusions:
- TSL2109 is a potent and selective DYRK2 inhibitor with significant anticancer activity against prostate cancer.
- TSL2109 shows potential in overcoming therapeutic resistance, addressing a critical unmet clinical need.
- TSL2109 has advanced to clinical trials, indicating its therapeutic promise for prostate cancer patients.
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