4.5 Article

A Cell-Based Target Engagement Assay for the Identification of Cereblon E3 Ubiquitin Ligase Ligands and Their Application in HDAC6 Degraders

Journal

CELL CHEMICAL BIOLOGY
Volume 27, Issue 7, Pages 866-+

Publisher

CELL PRESS
DOI: 10.1016/j.chembiol.2020.04.008

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Funding

  1. University of Wisconsin Carbone Cancer Center's (UWCCC) Consultation Panel
  2. NIH P30 CA014520-UW Comprehensive Cancer Center Support (CCSG)

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Proteolysis-targeting chimeras (PROTACs) is a paradigm shift for small-molecule drug discovery. However, limited E3 ubiquitin ligase ligands with cellular activity are available. In vitro binding assays involve the expression and purification of a large amount of proteins and they often yield ligands that are inactive in cell-based assays due to poor cell permeability, stability, and other reasons. Herein, we report the development of a practical and efficient cell-based target engagement assay to evaluate the binding affinity of a small library of cereblon ligands to its E3 ligase in cells. Selected cell-permeable E3 ligase ligands derived from this assay are then used to construct HDAC6 degraders with cellular protein degradation activity. Because the assay does not involve any genetic engineering, it is relatively easy to transfer from one cell type to a different one.

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