palbociclib and pomalidomide

A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. A design principle as "match/mismatch" was proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable CDK6 degradation potential were generated by linking CDK6 inhibitor palbociclib and E3 ligase CRBN recruiter pomalidomide. The PROTAC strongly inhibited proliferation of hematopoietic cancer cells including multiple myeloma and robustly degraded copy-amplified/mutated forms of CDK6, indicating future potential clinical applications.

Topics: Angiogenesis Inhibitors; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 6; Hematologic Neoplasms; HL-60 Cells; Humans; Molecular Structure; Piperazines; Protein Kinase Inhibitors; Proteolysis; Pyridines; Small Molecule Libraries; Thalidomide; THP-1 Cells; Ubiquitin-Protein Ligases