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

Area of Science:

• Oncology
• Pharmacology
• Drug Development

Background:

• Ovarian cancer treatment faces challenges like platinum resistance, recurrence, and micrometastatic disease.
• Conventional chemotherapy has limitations in overcoming these clinical obstacles.

Purpose of the Study:

• To introduce AP-604, a platinum(II)-based compound developed using the Targeted Drug Conjugate (TDC) strategy.
• To evaluate the efficacy and safety of AP-604 in preclinical models of ovarian cancer.

Main Methods:

• Assessed PIKfyve targeting capability and cytotoxicity of AP-604 against ovarian cancer cells (A2780).
• Investigated the antitumor mechanisms, including apoptosis induction, cell cycle arrest, and DNA damage.
• Conducted in vivo studies to compare AP-604's tumor suppression efficacy and safety against Cisplatin and Apilimod.

Main Results:

• AP-604 demonstrated potent PIKfyve targeting (IC50 = 15.4 ± 1.3 nM) and significant cytotoxicity (IC50 = 2.2 ± 0.4 μM).
• Mechanistic studies revealed concurrent apoptosis activation and S phase cell cycle arrest, with enhanced platinum accumulation and DNA damage.
• In vivo, AP-604 showed superior tumor suppression compared to Cisplatin and Apilimod without significant histopathological damage.

Conclusions:

• AP-604 exhibits a multi-mode antitumor action, overcoming limitations of conventional chemotherapy.
• AP-604 presents potential as a promising drug candidate for ovarian cancer, offering enhanced efficacy and a favorable safety profile.