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- Title
Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors.
- Authors
Wittlinger, Florian; Ogboo, Blessing C.; Shevchenko, Ekaterina; Damghani, Tahereh; Pham, Calvin D.; Schaeffner, Ilse K.; Oligny, Brandon T.; Chitnis, Surbhi P.; Beyett, Tyler S.; Rasch, Alexander; Buckley, Brian; Urul, Daniel A.; Shaurova, Tatiana; May, Earl W.; Schaefer, Erik M.; Eck, Michael J.; Hershberger, Pamela A.; Poso, Antti; Laufer, Stefan A.; Heppner, David E.
- Abstract
Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency (~60 pM) against the drug-resistant EGFR L858R/T790M and L858R/T790M/C797S, which was superadditive as compared with the parent molecules. The enhanced potency is attributed to factors stemming from the linker connection to the allosteric-site group and informs strategies to engineer linkers in bivalent agent design. Bivalent molecules comprising dual functional motifs often exhibit strong target binding, however arriving at the optimal structure is challenging. Here, the authors employ EGFR as a model system for understanding a subtle difference in the linker structure of bivalent inhibitors to enhance binding against drug-resistant EGFR mutants.
- Subjects
KINASE inhibitors; EPIDERMAL growth factor receptors; CRYSTAL structure
- Publication
Communications Chemistry, 2024, Vol 7, Issue 1, p1
- ISSN
2399-3669
- Publication type
Article
- DOI
10.1038/s42004-024-01108-3