Pyrrolidinium Fullerenes as YTHDF1 Inhibitors for Targeted Tumor Therapy.

Abstract

Cancer remains a leading cause of global morbidity and mortality, necessitating the development of novel targeted therapies. This study explores the therapeutic potential of pyrrolidinium fullerenes as YTH N⁶-methyladenosine RNA binding protein 1 (YTHDF1) inhibitors for cancer treatment. A series of functionalized pyrrolidinium fullerenes is synthesized and characterized, including C₆₀-(N,N-dimethyl-pyrrolidinium iodide) (NDMPFI), C₆₀-(N-methyl-N-benzyl-pyrrolidinium iodide) (NMBPFI), and C₆₀-(N-methyl-N-hydroxyethyl-pyrrolidinium iodide) (NMHPFI). These compounds exhibited strong binding affinity to YTHDF1, as confirmed by surface plasmon resonance (SPR) and molecular dynamics (MD) simulations. Mechanistic studies demonstrated that NDMPFI effectively suppressed cancer cell proliferation by inducing G0/G1 cell cycle arrest, downregulating key cell cycle regulators, including Cyclin D1, CDK4, and c-Myc, while also inhibiting epithelial-mesenchymal transition (EMT). Moreover, NDMPFI promoted proteasome-mediated degradation of YTHDF1, reducing the expression of downstream targets such as E2F8 and contributing to tumor growth inhibition. In vivo studies further validated its efficacy, showing significant tumor suppression in a lung cancer model without observable systemic toxicity. Collectively, these findings highlight pyrrolidinium fullerenes as promising candidates for targeted cancer therapy, paving the way for further development of YTHDF1 inhibitors as novel anticancer agents.