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

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 tyros

SUBMITTER: Burslem GM 

PROVIDER: S-EPMC5831399 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature