Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies

Small-molecule kinase modulators are an expanding class of compounds with broad impact on biology and medicine. However, although currently 100 inhibitors are FDA approved, many disease-linked kinases remain intractable to conventional therapeutic approaches. Key challenges include selectivity, modulation of scaffolding functions and overcoming drug resistance. Here, we review the expanding toolkit for kinase modulation, comparing traditional ATP-site inhibitors with emerging classes of allosteric modulators and proximity-inducing molecules such as molecular glues and heterobivalent degraders. Through representative case studies, we illustrate how these novel chemical approaches can overcome the limitations of traditional inhibitors and discuss future innovations poised to deliver the next generation of kinase-targeted therapies.