Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML
Open accessAbstract
The design of selective small molecules is often stymied by similar ligand binding pockets. Here, we report BSJ-03-123, a phthalimide-based degrader that exploits protein-interface determinants to achieve proteome-wide selectivity for the degradation of cyclin-dependent kinase 6 (CDK6). Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and transcriptomics and phosphoproteomics profiling of acute degradation of CDK6 enabled dynamic mapping of its immediate role in coordinating signaling and transcription.
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Several mechanisms contribute to increased selectivity of PROTACs, including steric incapability of some targets to form a productive ternary complex, or lack of a suitably positioned lysine residue for ubiquitination.
“Several mechanisms have been shown to contribute to this increase in selectivity. This includes steric incapability of some targets to form a productive ternary complex, or lack of a suitably positioned lysine residue for ubiquitination.62−69”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [67]
Beginning a targeted protein degrader discovery project with solid prior knowledge of optimal chemotype-target pairs can rapidly speed up hit-to-lead time.
“Beginning a targeted protein degrader discovery project with solid prior knowledge of optimal chemotype-target pairs can rapidly speed up hit-to-lead time (Brand et al., 2019; Cromm et al., 2018; Dobrovolsky et al., 2019; Jiang et al., 2019; Li et al., 2019; Olson et al., 2018).”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Brand et al., 2019
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 [70]
BSJ-03-123 selectively degrades CDK6 but not CDK4 in AML cell lines because it forms a ternary complex with CDK6 and CRBN but not with CDK4 and CRBN.
“BSJ-03-123, a CRBN-based CDK6 degrader, was reported to selectively degrade CDK6 but not CDK4 in AML cell lines because it can form a ternary complex with CDK6 and CRBN but not with CDK4 and CRBN [121].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [121]
Even when a PROTAC with exquisite selectivity is developed, the determinants driving its specificity profile often remain complex, obscure or puzzling.
“Even when a PROTAC with exquisite selectivity is developed, the determinants driving its specificity profile often remain complex, obscure or puzzling 29,30 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [30]
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- Authors
- Brand, M., Jiang, B., Bauer, S., Donovan, K. A., Liang, Y., Wang, E. S., Nowak, R. P., Yuan, J. C., Zhang, T., Kwiatkowski, N., Müller, A. C., Fischer, E. S., Gray, N. S., & Winter, G. E.
- Affiliations
- Austrian Academy of Sciences (AT)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Gray, Nathanael S.
- Winter, Georg E.
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 26
- Issue
- 2
- Pages
- 300-306.e9
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC6444916
- OpenAlex
- W2908027391
- Cited by
- 258
- References
- 24
- Citations by year
- 2026: 24 · 2025: 28 · 2024: 29 · 2023: 22 · 2022: 38 · 2021: 43 · 2020: 57 · 2019: 17
- FWCI
- 10.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Austrian Academy of Sciences
- FWF
- NIH (CA154303-06)
- NCI (R01 CA214608-02)
- Damon Runyon Cancer Research Foundation (DRR-50-18)
- Novartis Pharmaceuticals
- Astellas Pharma
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- CDK6, acute myeloid leukemia, protein degradation, phosphoproteomics, transcriptomics
- MeSH terms
- Humans, Phthalimides, Signal Transduction, Leukemia, Myeloid, Acute, Gene Expression, Cell Line, Tumor, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Gene Regulatory Networks, Small Molecule Libraries
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