Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML. Issue 2 (21st February 2019) - Brand, Matthias
Summary: The design of selective small molecules is often stymied by similar ligand binding pockets. Here, we report BSJ-03-123, a phthalimide-based degrader that exploits protein-interface determinants to achieve proteome-wide selectivity for the degradation of cyclin-dependent kinase 6 (CDK6). Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and transcriptomics and phosphoproteomics profiling of acute degradation of CDK6 enabled dynamic mapping of its immediate role in coordinating signaling and transcription. Graphical Abstract: Highlights: Development of a CDK6-selective small-molecule degrader Mechanistically understood selectivity via differential ternary complex formation Profiling of consequences of CDK6 degradation on signaling and gene regulation Precise exploitation of genetic dependencies through homolog-selective degradation Abstract : Brand et al. describe BSJ-03-123, a degrader with proteome-wide selectivity for CDK6. Specificity emerges from differential ternary complex formation with the E3 ligase CRL4 CRBN . BSJ-03-123 exploits a dependency of AML cells on CDK6, and rapid degradation allowed assaying the role of CDK6 in coordinating signaling and gene control in AML.