Patterns of substrate affinity, competition, and degradation kinetics underlie biological activity of thalidomide analogs.

ABSTRACT: Pharmacologic agents that modulate ubiquitin ligase activity to induce protein degradation are a major new class of therapeutic agents, active in a number of hematologic malignancies. However, we currently have a limited understanding of the determinants of activity of these agents and how resistance develops. We developed and used a novel quantitative, targeted mass spectrometry (MS) assay to determine the relative activities, kinetics, and cell-type specificity of thalidomide and 4 analogs, all but 1 of which are in clinical use or clinical trials for hematologic malignancies. Thalidomide analogs bind the CRL4^CRBN ubiquitin ligase and induce degradation of particular proteins, but each of the molecules studied has distinct patterns of substrate specificity that likely underlie

SUBMITTER: Sperling AS 

PROVIDER: S-EPMC6624968 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature