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Heterobifunctional Molecules Induce Dephosphorylation of Kinases–A Proof of Concept Study

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journal contribution
posted on 14.01.2020, 15:34 by Sayumi Yamazoe, Jeffrey Tom, Yue Fu, Wenqiong Wu, Liang Zeng, Changlei Sun, Qi Liu, Jie Lin, Kui Lin, Wayne J. Fairbrother, Steven T. Staben
Heterobifunctional molecules have proven powerful tools to induce ligase-dependent ubiquitination of target proteins. We describe here a chemical strategy for controlling a different post-translational modification (PTM): phosphorylation. Heterobifunctional molecules were designed to promote the proximity of a protein phosphatase (PP1) to protein targets. The synthesized molecules induced the PP1-dependent dephosphorylation of AKT and EGFR. To our knowledge, this work represents the first examples of small molecules recruiting non-native partners to induce removal of a PTM.