The DOI matches its Crossref record; 28 of the 29 references it cites were found in a registry or an index.
Selective degradation of CDK6 by a palbociclib based PROTAC
Open accessAbstract
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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“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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BindingDB Entry 50018749: PROTAC: A promising technology for cancer treatment.
BindingDB (2024) · UC San Diego · doi:10.7270/q2q244hq
BindingDB Entry 50018659: Developments of CRBN-based PROTACs as potential therapeutic agents.
BindingDB (2024) · UC San Diego · doi:10.7270/q27948wc
BindingDB (2025) · UC San Diego · doi:10.7270/q2vh5th3
BindingDB (2021) · UC San Diego · doi:10.7270/q2jw8jf1
BindingDB (2022) · UC San Diego · doi:10.7270/q2348q6b
BindingDB Entry 50017151: Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery Efforts.
BindingDB (2023) · UC San Diego · doi:10.7270/q2bv7mpd
BindingDB (2023) · UC San Diego · doi:10.7270/q2k93cjv
BindingDB (2021) · UC San Diego · doi:10.7270/q23f4t3t
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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