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Cell Chem Biol. 2018 Jan 18;25(1):67-77.e3. doi: 10.1016/j.chembiol.2017.09.009. Epub 2017 Nov 9.

The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study.

Author information

1
Department of Molecular, Cellular, and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT, USA.
2
Arvinas, LLC, 5 Science Park, New Haven, CT, USA.
3
Department of Molecular, Cellular, and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT, USA; Departments of Chemistry and Pharmacology, Yale University, New Haven, CT, USA. Electronic address: craig.crews@yale.edu.

Abstract

Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach.

KEYWORDS:

EGFR; HER2; PROTAC; VHL; c-Met; receptor tyrosine kinases; targeted degradation

PMID:
29129716
PMCID:
PMC5831399
[Available on 2019-01-18]
DOI:
10.1016/j.chembiol.2017.09.009

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