Bivalent target-binding bioPROTACs induce potent degradation of oncogenic SHP2
Name
PIIS0021925824021173.pdf
Description
Published version
Size
1.68 MB
Format
Adobe PDF
Checksum (MD5)
c4f909acb860514e3974dbed0d293d43
Author(s)
Hoffman, Megan
Krum, David
Wittrup, K Dane
Date Issued
September 2024
Journal
Journal of Biological Chemistry
Publisher
Elsevier BV
Citation
Hoffman, Megan, Krum, David and Wittrup, K Dane. 2024. "Bivalent target-binding bioPROTACs induce potent degradation of oncogenic SHP2." Journal of Biological Chemistry, 300 (9).
Version
Final published version
Abstract
Targeted protein degradation is an emergent and rapidly evolving therapeutic strategy. In particular, biologics-based targeted degradation modalities (bioPROTACs) are relatively under explored compared to small molecules. Here, we investigate how target affinity, cellular localization, and valency of bioPROTACs impact efficacy of targeted degradation of the oncogenic phosphatase src-homology 2 containing protein tyrosine phosphatase-2 (SHP2). We identify bivalent recruitment of SHP2 by bioPROTACs as a broadly applicable strategy to improve potency. Moreover, we demonstrate that SHP2-targeted bioPROTACs can effectively counteract gain-of-function SHP2 mutants present in cancer, which are otherwise challenging to selectively target with small molecule constructs. Overall, this study demonstrates the utility of bioPROTACs for challenging targets, and further explicates design principles for therapeutic bioPROTACs.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivatives
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DOI of Published Version
10.1016/j.jbc.2024.107616
