Targeting Ribosome\nBiogenesis for Cancer Therapy with\nOral Platinum Complexes

Cancer cells often upregulate ribosome biogenesis to\nmeet increased\nprotein synthesis demands for rapid proliferation; therefore, targeting\nribosome biogenesis has emerged as a promising cancer therapeutic\nstrategy. Herein, we introduce two Pt complexes, ataluren monosubstituted\nplatinum(IV) (SPA, formula: c,c,t,-[Pt(NH<sub>3</sub>)<sub>2</sub>Cl<sub>2</sub>(OH)(C<sub>15</sub>H<sub>8</sub>FN<sub>2</sub>O<sub>3</sub>)], where C<sub>15</sub>H<sub>8</sub>FN<sub>2</sub>O<sub>3</sub> = ataluren) and ataluren bisubstituted platinum(IV) complex (DPA,\nformula: c,c,t,-[Pt(NH<sub>3</sub>)<sub>2</sub>Cl<sub>2</sub>(C<sub>15</sub>H<sub>8</sub>FN<sub>2</sub>O<sub>3</sub>)<sub>2</sub>], where\nC<sub>15</sub>H<sub>8</sub>FN<sub>2</sub>O<sub>3</sub> = ataluren),\nwhich effectively suppress ribosome biogenesis by inhibiting 47s pre-RNA\nexpression. Furthermore, SPA and DPA induce nucleolar stress by dispersing\nnucleolar protein NPM1, ultimately inhibiting protein generation in\ntumor cells. More importantly, DPA exhibits superior cytotoxicity\nto various cancer cells and in vivo antitumor efficacy compared to\ncisplatin, with lower systemic toxicity. Notably, in clinically relevant\nmodels, including orthotopic hepatic tumor-bearing mice and patient-derived\nbladder cancer organoids, DPA outperforms cisplatin significantly,\nwith the added benefit of oral administration, enhancing clinical\nfeasibility. To our knowledge, DPA emerges as the pioneering Pt(IV)\nagent targeting the ribosome, providing new insights for designing\nnext-generation metal-based therapeutics.