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A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader.

Hai-Tsang Huang1, Dennis Dobrovolsky1, Joshiawa Paulk2

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Cell Chemical Biology
|November 14, 2017
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Summary

This study shows that targeted protein degradation using cereblon (CRBN) binders can degrade many kinases. Researchers developed selective degraders for FLT3 and BTK, offering potential disease treatments.

Keywords:
BTKFLT3chemoproteomicsdrug designkinaseprotein degradation

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Biochemistry

Background:

  • Targeted protein degradation via E3 ubiquitin ligase recruitment is a novel therapeutic strategy.
  • The general applicability of this approach to diverse protein targets remains largely unexplored.

Purpose of the Study:

  • To investigate the degradability of kinases using a novel multi-kinase degrader.
  • To identify specific kinase targets amenable to degradation and develop selective degraders for therapeutic applications.

Main Methods:

  • Design and synthesis of a heterobifunctional molecule linking a kinase inhibitor to a cereblon (CRBN) ligand.
  • Quantitative proteomics to identify protein targets and assess degradation.
  • Development of selective degraders for identified kinase targets.

Main Results:

  • Discovery of 28 degradable kinases, including Bruton's tyrosine kinase (BTK), Janus kinase (JAK), and cyclin-dependent kinases (CDKs).
  • Demonstration that target engagement alone does not guarantee degradation, highlighting the need for specific molecular features.
  • Successful development of selective degraders for FMS-like tyrosine kinase 3 (FLT3) and BTK.

Conclusions:

  • The study provides an efficient method for identifying degradable kinase targets within a gene family.
  • Developed selective FLT3 and BTK degraders show promise for improving disease treatment strategies.
  • This work advances the field of targeted protein degradation for drug discovery and pre-clinical development.