Chemical Scaffolds Driving Modern Anticancer Drug Discovery and Radiotheranostics: Structural Determinants, Translational Opportunities and Future Perspectives

Abstract

Cancer remains one of the leading causes of morbidity and mortality worldwide despite advances in molecular oncology and targeted therapeutics. The growing demand for precision medicine has accelerated the development of radiotheranostics, an emerging paradigm that integrates molecular imaging and targeted radionuclide therapy. In parallel, medicinal chemistry continues to generate structurally diverse small-molecule scaffolds capable of modulating key oncogenic pathways. Increasing evidence indicates that certain chemical scaffolds possess intrinsic properties that extend beyond conventional anticancer activity and support their translation into radiotheranostic applications. This review examines major scaffold classes driving contemporary anticancer drug discovery, including thiosemicarbazones, heterocyclic compounds, metal-based agents, hybrid molecules, and multifunctional platforms. Particular attention is given to the structural features governing biological activity, target selectivity, metal coordination, and radiolabeling potential. The review further highlights the mechanistic convergence between scaffold-mediated anticancer effects and radionuclide-induced cytotoxicity, emphasizing shared pathways involving DNA damage, oxidative stress, inhibition of DNA repair, and modulation of oncogenic signaling. Based on these observations, a scaffold-centered framework for radiotheranostic development is proposed, with perspectives on hybrid molecular design, copper-based theranostic systems, and artificial intelligence-assisted ligand discovery. By integrating medicinal chemistry, molecular oncology, and nuclear medicine, this review outlines structural principles that may facilitate the rational design of next-generation precision anticancer agents and radiotheranostic platforms.