Targeting Ribosome Biogenesis for Cancer Therapy with Oral Platinum Complexes.

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Molecular Therapeutics

Background:

• Cancer cells require enhanced ribosome biogenesis for proliferation.
• Targeting ribosome biogenesis is a viable cancer treatment strategy.

Purpose of the Study:

• To develop novel platinum(IV) complexes targeting ribosome biogenesis.
• To evaluate the efficacy and toxicity of these complexes in cancer models.

Main Methods:

• Synthesis and characterization of ataluren monosubstituted platinum(IV) (SPA) and bisubstituted platinum(IV) (DPA) complexes.
• Assessment of 47s pre-RNA inhibition and NPM1 dispersion.
• Evaluation of cytotoxicity, in vivo antitumor efficacy, and systemic toxicity in relevant cancer models.

Main Results:

• SPA and DPA effectively suppress ribosome biogenesis by inhibiting 47s pre-RNA.
• Both complexes induce nucleolar stress via NPM1 dispersion, inhibiting protein synthesis.
• DPA demonstrates superior cytotoxicity and in vivo antitumor activity compared to cisplatin, with reduced systemic toxicity.
• DPA shows significant efficacy in orthotopic hepatic tumors and patient-derived bladder cancer organoids, with oral administration feasibility.

Conclusions:

• Ataluren-based platinum(IV) complexes, particularly DPA, represent a novel therapeutic strategy targeting ribosome biogenesis.
• DPA exhibits promising preclinical efficacy and safety, outperforming cisplatin.
• DPA is the first Pt(IV) agent targeting the ribosome, offering new avenues for metal-based cancer therapeutics.