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

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 pro...

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Published inJournal of medicinal chemistry Vol. 63; no. 6; pp. 2807 - 2813
Main Authors Yamazoe, Sayumi, Tom, Jeffrey, Fu, Yue, Wu, Wenqiong, Zeng, Liang, Sun, Changlei, Liu, Qi, Lin, Jie, Lin, Kui, Fairbrother, Wayne J, Staben, Steven T
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 26.03.2020
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
ACTIVATION
PROTEIN
DEGRADATION
PROTACS
INHIBITORS
DISCOVERY
PEPTIDE
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Summary: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.
Bibliography:ObjectType-Article-1
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content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b01167