Drug Hunting at the Nexus of Medicinal Chemistry and Chemical Biology and the Discovery of Novel Therapeutic Modalities.

Abstract

Small molecules designed to modulate protein function have been remarkably successful in advancing human health. As the frontiers of medicine and understanding of disease pathogenesis continue to expand, small molecule scientists must also pursue the development of novel therapeutic modalities beyond functional protein modulation to address diseases of unmet medical need. In this vein, this Perspective will highlight two emerging modalities, selective mRNA splice modulation and targeted protein degradation, as mechanisms that affect protein abundance, rather than protein function, to broaden the scope of low-molecular-weight treatable diseases. Key to the elucidation and development of these mechanisms was the interplay and contemporaneous efforts in medicinal chemistry and chemical biology. Continued research at the intersection of these two fields will be critical for the identification of novel targets and mechanisms toward the development of the next generation of small molecule therapeutics.