Medicinal Chemistry Strategies for Targeting RNA-Binding Proteins: Design, Optimization, and Therapeutic Potential

Abstract

Abstract RNA-binding proteins (RBPs) are essential regulators of post-transcriptional gene expression whose disruption contributes broadly to tumor initiation, progression, and therapeutic resistance. Through their control of RNA splicing, stability, translation, and epitranscriptomic modification, these proteins orchestrate oncogenic networks that sustain hallmark cancer phenotypes. This central role has stimulated intensive efforts to develop small-molecule RBP inhibitors, yielding mechanistically diverse compounds against m6A pathway components and classical oncogenic RBPs with demonstrated efficacy in preclinical models. However, substantial challenges remain, including achieving high target selectivity, optimizing drug-like properties, and addressing adaptive resistance mechanisms. This article examines recent advances in RBP-targeted therapeutics, highlighting design strategies, structural mechanisms, and key obstacles on the path toward clinical application.