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. 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