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A design approach for bitopic kinase inhibitors

Nature Bioinformatics AI Jack W. Stevenson, Kevin Lou, Joshua A. Reynolds, Ian R. Outhwaite, Kenneth Huang, Ivan Sokirniy, Sky Y. J. Peterson, Amir Z. Munir, Celine D. Wang, Haider Inam, Emma L. Gebauer, Ariel Leyte-Vidal, Anastasiia Grynyova, Sydney M. Figueroa, Matthew G. Rees, Melissa M. Ronan, Fernando Salangsang, Yan Zeng, Veronica Steri, Jennifer A. Roth, Neil P. Shah, Ignacia Echeverria, Andrej Šali, Ziyang Zhang, Javid J. Moslehi, Markus A. Seeliger, Justin R. Pritchard, Kevan M. Shokat 2026-09-23

TL;DR - This Nature study presents a design strategy for bitopic kinase inhibitors that simultaneously engage two binding regions. Applying it to ABL1 and EGFR produced an ABL1 inhibitor with improved activity against resistance mutations and reduced off-target toxicity.

The approach systematically evaluates ligand choice, linkage vector, and linker length.
Bitopic inhibitors were developed for both ABL1 and EGFR kinases.
The reported ABL1 inhibitor showed enhanced activity against resistance mutations.
Reduced off-target toxicity suggests potential for more selective kinase therapies.

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