KCS

Targeted protein degradation (TPD) such as PROTAC, AUTAC, and LYTAC is a promising and emerging therapeutic modality. Targeted protein degradation (TPD) adopting small molecule ligands utilizes ubiquitin proteasome system (UPS) or autophagy lysosomal pathway (ALP). Overactivated protein kinases caused by mutations cause various diseases such as cancer and small molecule kinase inhibitors have intensively been discovered for targeted therapy. Despite the increasing number of small molecule kinase inhibitors approved or in clinical investigations, only 7% of the human kinome has been therapeutically explored. Furthermore, despite the widespread exploration of TPD as a novel pharmacological modality, it still remains hard to predict which protein kinases are tractable and which may prove recalcitrant to this approach. In order to provide useful degrader chemical probes and clinically relevant leads across the kinome, we synthesized a variety of different kinds PROTACs of which warheads are different chemo-types of small molecule kinase inhibitors and chemoproteomic technologies were utilized to annotate the degradable kinome. Our expansive dataset provides novel PROTACs for degrading over 200 kinases. An integrated guideline for designing efficiently novel kinase PROTACs is provided by making the first map that reveals the correlation between chemical structure of the kinase PROTACs and the properties including degradability/selectivity. Moreover, novel AUTACs to degrade effectively disease-associated aggregated proteins will be briefly presented.