Homolog-selective degradation as a strategy to probe the function of CDK6 in AML

The design of selective small-molecules is often stymied by similar ligand binding pockets. Here we report the first cyclin-dependent kinase 6 (CDK6) degrader, BSJ-03-123, that uses phthalimide-conjugation to exploit protein-interface determinants to achieve proteome-wide degradation selectivity. Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and coupling acute degradation with transcriptomics and phosphoproteomics enabled dynamic mapping of the immediate role of CDK6 in coordinating signaling and transcription. Overall design: RNA-seq of MV4-11 cells treated for 6h with the CDK4/6 inhibitor palbociclib or the CDK6-specific phthalimide conjugates BSJ-03-123 and YKL-06-102