Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies
Summary
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 al
Content
# Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies
*Published: 2026 Apr 28*
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.
DOI: 10.1038/s41573-026-01411-9