ABSTRACT
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.
Subject(s)
Cyclin-Dependent Kinase 6/antagonists & inhibitors , Piperazines/pharmacology , Pyridines/pharmacology , Small Molecule Libraries/pharmacology , Thalidomide/analogs & derivatives , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 6/chemistry , Cyclin-Dependent Kinase 6/metabolism , HL-60 Cells , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/pathology , Hematologic Neoplasms/prevention & control , Humans , Molecular Structure , Piperazines/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proteolysis , Pyridines/chemistry , Small Molecule Libraries/chemistry , THP-1 Cells , Thalidomide/chemistry , Thalidomide/pharmacology , Ubiquitin-Protein Ligases/metabolismABSTRACT
In the original publication the title of X axis in figure 1G is incorrectly published as "Compound (µmol/L)". The correct title of X axis in figure 1G should be read as "Compound (nmol/L)".
