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Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors

Medicine and Health

Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors

F. Wittlinger, B. C. Ogboo, et al.

This groundbreaking study unveiled a series of bivalent EGFR inhibitors, showcasing their remarkable ability to target both ATP and allosteric pockets with enhanced potency against drug-resistant mutants. Conducted by a dedicated team of researchers, their innovative linker design has opened new avenues in bivalent agent strategies, providing insights that may change the landscape of cancer treatment.

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Playback language: English
Abstract
Bivalent molecules, with groups linked through bridging linkers, often exhibit strong target binding. This study reports a set of alternatively linked bivalent EGFR inhibitors occupying the ATP substrate and allosteric pockets. Crystal structures reveal successful linker spanning of these sites. A re-engineered linker yielded a compound with significantly higher potency (-60 pM) against drug-resistant EGFR mutants, exhibiting superadditive effects. Enhanced potency is attributed to linker connection and informs bivalent agent design strategies.
Publisher
Communications Chemistry
Published On
Feb 20, 2024
Authors
Florian Wittlinger, Blessing C. Ogboo, Ekaterina Shevchenko, Tahereh Damghani, Calvin D. Pham, Ilse K. Schaeffner, Brandon T. Oligny, Surbhi P. Chitnis, Tyler S. Beyett, Alexander Rasch, Brian Buckley, Daniel A. Urul, Tatiana Shaurova, Earl W. May, Erik M. Schaefer, Michael J. Eck, Pamela A. Hershberger, Antti Poso, Stefan A. Laufer, David E. Heppner
Tags
bivalent molecules
EGFR inhibitors
drug-resistant mutants
linker design
potency
cancer research
allosteric pockets

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