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

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.