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Selective degradation of CDK6 by a palbociclib based PROTAC
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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.
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Multiple studies have described numerous CRBN-recruiting dual-selective degraders and CDK6-selective degraders, but none report CDK4-selective degraders; the only reported CDK4-selective degraders are built on ribociclib.
“Whereas multiple studies have described numerous CRBN-recruiting dual-selective degraders and CDK6-selective degraders 70–73, none report CDK4-selective degraders; the only reported CDK4-selective degraders are built on a slightly different warhead, ribociclib 74.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [73]
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Metadata
- Authors
- Rana, S., Bendjennat, M., Kour, S., King, H. M., Kizhake, S., Zahid, M., & Natarajan, A.
- Affiliations
- University of Nebraska Medical Center (US)
- Fred and Pamela Buffett Cancer Center (US)
- Corresponding author
- Rana, Sandeep
- Natarajan, Amarnath
- ORCID
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 29
- Issue
- 11
- Pages
- 1375-1379
- ISSN
- 0960-894X (ISSN-L)
- PMC
- PMC6487213
- OpenAlex
- W2924113881
- Cited by
- 135
- References
- 29
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 13 · 2023: 13 · 2022: 20 · 2021: 25 · 2020: 31 · 2019: 4
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA197999, P30CA036727)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- palbociclib, PROTACs, CDK4, kinase-independent function, selective protein degradation, ATP binding site, kinase inhibitors, competitive binding
- MeSH terms
- Dose-Response Relationship, Drug, Humans, Models, Molecular, Piperazines, Pyridines, Structure-Activity Relationship, Molecular Structure, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 6, Proteolysis
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