Beyond Inhibition: Emerging Small-Molecule Modalities in Oncology (Molecular Glues, Covalents, and Radiotheranostics)

Abstract

Background: Small-molecule drugs have transformed oncology, but conventional inhibitors are limited by resistance, restricted target scope, and declining durability. Methods: We reviewed emerging small-molecule modalities—molecular glues, covalent inhibitors, and radiotheranostics—focusing on their mechanisms, clinical applications, and translational challenges. Key clinical trials and representative examples were identified from recent oncology literature. Results: Molecular glues enable targeted degradation of previously undruggable proteins, with clinical success in multiple myeloma (IMiDs). Covalent inhibitors achieve durable suppression of oncogenic drivers such as KRAS^G12C and BTK, as shown in CodeBreaK100 (sotorasib; N=126; ORR 37%). Radiotheranostics combine imaging and therapy, exemplified by VISION (PSMA-617; N=831; OS HR 0.62) and NETTER-1 (Lutathera; N=229; PFS HR 0.21). Collectively, these modalities expand the druggable proteome, improve durability, and advance precision oncology. Conclusion: Emerging small-molecule approaches mark a paradigm shift from inhibition alone to targeted degradation, durable covalent engagement, and diagnostic–therapeutic hybrids. Future priorities include improving selectivity, biomarker integration, scalable manufacturing, and equitable global access.