The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.
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 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]
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Cites
Meyers, R. M., Bryan, J. G., McFarland, J. M., Weir, B. A., Sizemore, A. E., Xu, H., Dharia, N. V., Montgomery, P. G., Cowley, G. S., Pantel, S., et al. (2017) · Nature Genetics · doi:10.1038/ng.3984 · Cited by 1,952
Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
Krönke, J., Udeshi, N. D., Narla, A., Grauman, P., Hurst, S. N., McConkey, M., Svinkina, T., Heckl, D., Comer, E., Li, X., et al. (2014) · Science · doi:10.1126/science.1244851 · Cited by 1,879
Phthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760
Self-citationThe Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins
Lu, G., Middleton, R. E., Sun, H., Naniong, M., Ott, C. J., Mitsiades, C. S., Wong, K.-K., Bradner, J. E., & Kaelin, W. G. (2014) · Science · doi:10.1126/science.1244917 · Cited by 1,583
Structural basis of PROTAC cooperative recognition for selective protein degradation
Gadd, M. S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D. J., Zengerle, M., & Ciulli, A. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2329 · Cited by 1,242
Fry, D. W., Harvey, P. J., Keller, P. R., Elliott, W. L., Meade, M., Trachet, E., Albassam, M., Zheng, X., Leopold, W. R., Pryer, N. K., et al. (2004) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.1427.3.11 · Cited by 1,236 · cited 1×
“Towards the development of CDK4/6 degraders, we chose palbociclib (palbo) as a starting point given its high selectivity and potency (Fry et al., 2004).”
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J. D., Crew, A. P., Coleman, K., et al. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.05.009 · Cited by 1,140
Treating cancer with selective CDK4/6 inhibitors
O'Leary, B., Finn, R. S., & Turner, N. C. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.26 · Cited by 1,137
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4
Zengerle, M., Chan, K.-H., & Ciulli, A. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00216 · Cited by 1,056
Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead
Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B. D., Ishchenko, A., & Crews, C. M. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.010 · Cited by 923
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Selective degradation of PARP2 by PROTACs via recruiting DCAF16 for triple-negative breast cancer
Pu, C., Tong, Y., Liu, Y., Lan, S., Wang, S., Yan, G., Zhang, H., Luo, D., Ma, X., Yu, S., et al. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114321 · Cited by 54
Kwiatkowski, N., Liang, T., Sha, Z., Collier, P. N., Yang, A., Sathappa, M., Paul, A., Su, L., Zheng, X., Aversa, R., et al. (2025) · Cell Chemical Biology · doi:10.1016/j.chembiol.2025.03.006 · Cited by 23
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Metadata
- 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
- Physical Sciences › Chemistry › Organic Chemistry › 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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