2. Academic Validation
  3. Bivalent target-binding bioPROTACs induce potent degradation of oncogenic SHP2

Bivalent target-binding bioPROTACs induce potent degradation of oncogenic SHP2

  • J Biol Chem. 2024 Jul 31;300(9):107616. doi: 10.1016/j.jbc.2024.107616.
Megan Hoffman 1,  David Krum 2,  K Dane Wittrup 3
Affiliations

Affiliations

  • 1 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 2 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 3 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. Electronic address: wittrup@mit.edu.
PMID: 39089586 DOI: 10.1016/j.jbc.2024.107616
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.

Keywords

BioPROTAC; E3 ubiquitin ligase; PROTAC; SHP2; SPOP; cancer; proteasome; protein degradation; protein engineering; targeted protein degradation.

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