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Selective degradation of CDK6 by a palbociclib based PROTAC.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Jun 01; Vol. 29 (11), pp. 1375-1379. Date of Electronic Publication: 2019 Mar 26. - Publication Year :
- 2019
-
Abstract
- Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Herein, we report a palbociclib based PROTAC that selectively degrades CDK6 while sparing the homolog CDK4. We used competition studies to characterize the binding and mechanism of CDK6 degradation.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Cyclin-Dependent Kinase 6 metabolism
Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Piperazines chemical synthesis
Piperazines chemistry
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Pyridines chemical synthesis
Pyridines chemistry
Structure-Activity Relationship
Cyclin-Dependent Kinase 6 antagonists & inhibitors
Piperazines pharmacology
Protein Kinase Inhibitors pharmacology
Proteolysis drug effects
Pyridines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 29
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 30935795
- Full Text :
- https://doi.org/10.1016/j.bmcl.2019.03.035