Abstract
Targeted protein degradation (TPD) strategies open up new avenues for therapeutics and provide powerful tools for biological inquiry. Herein, we present a brand-new approach, termed heat shock protein 90 (HSP90)-mediated targeting chimeras (HEMTACs), to induce intracellular protein degradation by bridging a target protein to HSP90 to drive the downregulation of proteins. We successfully showcase HEMTACs for cyclin-dependent kinase 4 and 6 (CDK4/6) by using a flexible linker to connect the targeting warhead of CDK4/6 with the HSP90 ligand. Overall, our study delivers a series of evidence that HEMTACs can serve as a valuable addition to TPD strategies, most prominently proteolysis-targeting chimera technology.