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

Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein targets. In this study, we designed a multi-kinase degrader by conjugating a highly promiscuous kinase inhibitor with a cereblon-binding ligand, and used quantitative proteomics to discover 28 kinases, including BTK, PTK2, PTK2B, FLT3, AURKA, AURKB, TEC, ULK1, ITK, and nine members of the CDK family, as degradable. This set of kinases is only a fraction of the intracellular targets bound by the degrader, demonstrating that successful degradation requires more than target engagement. The results guided us to develop selective degraders for FLT3 and BTK, with potentials to improve disease treatment. Together, this study demonstrates an efficient approach to triage a gene family of interest to identify readily degradable targets for further studies and pre-clinical developments. [Display omitted] •Promiscuous degrader as a strategy to triage a gene family for tractable targets•Efficient degradation induced by degraders requires more than target engagement•Therapeutic targets BTK and FLT3 are susceptible to targeted degradation•A selective BTK degrader demonstrates prolonged pharmacodynamic effects Heterobifunctional protein degrader is an emerging pharmacological strategy. Using a multi-kinase degrader, Huang et al. greatly expanded the number of known degradable kinases, and demonstrated an efficient approach to triage a gene family for actionable targets with potential therapeutic impacts.