PIKfyve-specific Pt(II)-based targeted drug conjugate in treatment of ovarian cancer through multi-mode actions.

Ovarian cancer treatment has long been challenged by clinical obstacles including platinum resistance recurrence and incomplete eradication of micrometastatic lesions. This study presents a platinum(II)-based compound AP-604 through the "Targeted Drug Conjugate (TDC)" strategy to overcome the limitations inherent in conventional chemotherapy. Research indicated that AP-604 preserved potent PIKfyve targeting capability (IC50 = 15.4 ± 1.3 nM) while also exhibiting pronounced cytotoxicity against A2780 (IC50 = 2.2 ± 0.4 μM). Mechanistic investigations revealed a multi-mode antitumor action involving concurrent activation of the BCL-2/caspase-dependent apoptotic pathway and S phase specific cell cycle arrest, complemented by enhanced platinum accumulation that exacerbated DNA damage. In vivo tests showed that AP-604 at a high dose achieved stronger tumor suppression than Cisplatin, Apilimod, and their combination without inducing significant histopathological damage. These findings proved that AP-604 has potential as a promising drug candidate with enhanced efficacy and favorable safety profiles in treatment of ovarian cancer.