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Cited by 295Protein Degradation and InhibitorsHistone Deacetylase Inhibitors ResearchAdvanced Breast Cancer Therapies

Development of dual and selective degraders of cyclin-dependent kinases 4 and 6

Open access
Jiang, Baishan, Wang, Eric S., Donovan, Katherine A., Liang, Yanke, Fischer, Eric S., Zhang, Tinghu, Gray, Nathanael S.·2019·Angewandte Chemie International Edition
DOI 10.1002/anie.201901336PMC PMC7678623
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Abstract

Cyclin‐dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, and there are FDA‐approved CDK4/6 inhibitors for treating patients with metastatic breast cancer. However, due to conservation of their ATP‐binding sites, development of selective agents has remained elusive. Here, we report imide‐based degrader molecules capable of degrading both CDK4/6, or selectively degrading either CDK4 or CDK6. We were also able to tune the activity of these molecules against Ikaros (IKZF1) and Aiolos (IKZF3), which are well‐established targets of imide‐based degraders. We found that in mantle cell lymphoma cell lines, combined IKZF1/3 degradation with dual CDK4/6 degradation produced enhanced anti‐proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation. In summary, we report here the first compounds capable of inducing selective degradation of CDK4 and CDK6 as tools to pharmacologically dissect their distinct biological functions.

AI snapshot

Written from the paper’s full text.

TL;DR

The paper reports imide-based bifunctional degraders that recruit CRBN to induce dual CDK4/6 degradation or selective degradation of either CDK4 or CDK6, while also tuning IKZF1/3 degradation. In mantle cell lymphoma cell lines, combined CDK4/6 and IKZF1/3 degradation showed enhanced anti-proliferative effects compared with CDK4/6 inhibition, CDK4/6 degradation alone, or IKZF1/3 degradation.

Key findings

  • Palbociclib-, ribociclib-, and abemaciclib-based degraders were generated; most maintained biochemical IC50 values of 1–50 nM, and each inhibitor could be converted into active CDK4/6 degraders in Jurkat cells after 4 h treatment with 1 µM.
  • Selective degraders were identified: BSJ-01–187 selectively degraded CDK4, YKL-06–102 selectively degraded CDK6, and BSJ-02–162 degraded both CDK4 and CDK6. Analogs BSJ-03–204, BSJ-04–132, and BSJ-03–123 retained dual CDK4/6, selective CDK4, or selective CDK6 degradation, respectively, without degrading IKZF1/3.
  • Degradation was CRBN-dependent: in CRISPR/Cas9-generated Crbn−/− Jurkat cells, CDK4/6 and/or IKZF1/3 protein levels were unaffected, and 100 nM BSJ-02–162 induced G1 arrest in wildtype but not Crbn−/− Jurkat cells after 24 h, whereas 100 nM palbociclib induced G1 arrest in both.
  • In MCL cells, 1 µM BSJ-02–162 for 1 day degraded CDK4/6 and IKZF1/3, while BSJ-03–204 degraded only CDK4/6; both reduced phosphorylated Rb and induced G1 arrest. BSJ-02–162 showed increased anti-proliferative effects versus BSJ-03–204 in many MCL cell lines. In Molt4 proteomics at 250 nM for 5 h, BSJ-04–132 reduced CDK4 by ~1.9-fold, below the 2-fold threshold, but more than CDK6, IKZF1, and IKZF3.

Methods

  • Degraders were designed by attaching PEG or alkyl linkers to the piperazine 4-nitrogen of palbociclib, ribociclib, or abemaciclib, terminating at the 4- or 5-position of thalidomide as the CRBN-recruiting moiety.
  • Cellular assays used Jurkat cells (wildtype and Crbn−/−), Molt4 cells, Granta-519 cells, and a panel of MCL cell lines; readouts included enzymatic CDK4/6 kinase inhibition, immunoblotting, propidium iodide cell-cycle analysis, multiplexed mass spectrometry-based proteomics, and anti-proliferative assays.
  • Main analyses compared degrader-induced protein loss, CRBN dependence, cell-cycle effects, and proteome-wide selectivity, with a minimum 2-fold change threshold used for proteomic scatterplot depiction.

Limitations

  • Stated: structural analysis of kinase-degrader-CRBN ternary complexes will be required to reveal the basis for the observed CDK4 versus CDK6 selectivity.
  • Evident: all reported efficacy and degradation data are from cell lines; no in vivo animal or clinical data are reported.
  • Evident: the proteomics analysis used a minimum 2-fold change threshold, and CDK4 reduction by BSJ-04–132 (~1.9-fold) did not meet this threshold, so its selective CDK4 degradation was inferred from Table S2 rather than the scatterplot.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/anie.201901336

Cites

24 of 24 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 19 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In mantle cell lymphoma cell lines, combined IKZF1/3 degradation with dual CDK4/6 degradation exhibited enhanced anti-proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation.

    “We found that in mantle cell lymphoma cell lines, combined IKZF1/3 degradation with dual CDK4/6 degradation exhibited enhanced anti-proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation.”
    • Also stated in: § Abstract · boosted
      “We also discovered that simultaneously degrading CDK4/6 and IKZF1/3 demonstrated enhanced anti-proliferation effect in MCL cell lines in comparison to palbociclib, lenalidomide, or a selective CDK4/6 degrader, similar to what was observed with a previously reported BTK degrader that also targeted IKZF1/3[13c].”
    Quote in the paperSubstantial claim
  • Findingown data

    BSJ-01-187 selectively degraded CDK4.

    “In contrast, BSJ-01–187, a ribociclib-based degrader with a 4-carbon alkyl linker, selectively degraded CDK4 (Figure 3C)”
    Quote in the paperSubstantial claim
  • Findingown data

    YKL-06-102 induced selective degradation of CDK6.

    “while the extended PEG-3 linker of the palbociclib-derived compound YKL-06–102 induced selective degradation of CDK6 (Figure 3E).”
    Quote in the paperSubstantial claim
  • Findingown data

    BSJ-02-162 degraded both CDK4 and CDK6.

    “For example, BSJ-02–162, which consists of an alkyl linker conjugated to palbociclib, degraded both CDK4 and CDK6 (Figure 3A).”
    Quote in the paperSubstantial claim
  • Findingown data

    By varying linkers for CDK4/6-targeted degraders, the authors identified molecules capable of acutely and selectively degrading either CDK4 or CDK6.

    “Here, by varying the linkers for CDK4/6-targeted degraders, we identified molecules capable of acutely and selectively degrading either CDK4 or CDK6.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ATP-binding pockets of CDK4 and CDK6 are highly conserved/homologous, and current CDK4/6 inhibitors are approximately equipotent for both proteins, making selective inhibition difficult.
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Findingown data

    Treatment of isogenic Jurkat cells in which CRBN was deleted by CRISPR/Cas9 had no effect on the abundance of CDK4/6 and/or IKZF1/3 protein, demonstrating that degradation was dependent on CRBN.

    “Finally, we found that treatment of isogenic Jurkat cells in which CRBN was deleted by CRISPR/Cas9 had no effect on the abundance of CDK4/6 and/or IKZF1/3 protein, demonstrating that that degradation was dependent on CRBN (Figure 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment of Molt4 cells with BSJ-03-123 resulted in loss of CDK6, but not CDK4 or IKZF1/3.

    “Finally, treatment of Molt4 cells with BSJ-03–123 resulted in loss of CDK6, but not CDK4 or IKZF1/3 (Figure 5D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In cells treated with BSJ-04-132, CDK4 level was reduced to a greater extent than CDK6, IKZF1, and IKZF3, although CDK4 (~1.9-fold change) did not meet the minimum 2-fold change threshold.

    “In cells treated with BSJ-04–132, CDK4 (~1.9-fold change) did not meet our minimum 2-fold change threshold to be depicted on the scatterplot (Figure 5C), but its level was reduced to a greater extent than those of CDK6, IKZF1 and IKZF3 (Table S2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Treatment of Granta-519 cells with BSJ-02-162 resulted in pronounced loss of CDK4/6 and IKZF1/3 protein, while BSJ-03-204 only resulted in degradation of CDK4/6.

    “Treatment of Granta-519 cells with 1 µM BSJ-02–162 for 1d resulted in pronounced loss of CDK4/6 and IKZF1/3 protein, while treatment with BSJ-03–204 only resulted in degradation of CDK4/6 (Figure 6A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Profiling confirmed that the authors could achieve both dual and selective degradation of CDK4/6 across the proteome after acute compound treatment, and that they could tune degradation of IKZF1/3.

    “Thus, profiling confirmed that we could achieve both dual and selective degradation of CDK4/6 across the proteome after acute compound treatment, and that we could tune degradation of IKZF1/3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BSJ-02-162, BSJ-01-187, and YKL-06-102 all induced degradation of IKZF1/3.

    “found that BSJ-02–162, BSJ-01–187, and YKL-06–102 all induced degradation of IKZF1/3 (Figure 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The authors developed imide-based degrader molecules capable of degrading both CDK4 and CDK6, or selectively degrading either CDK4 or CDK6.

    “Here, we report imide-based degrader molecules capable of degrading both CDK4/6, or selectively degrading either CDK4 or CDK6.”
    • Also stated in: § Abstract · plain
      “Here, we generated CRBN-recruiting degraders and identified molecules capable of inducing both dual CDK4/6 and selective CDK4 or CDK6 degradation.”
    • Also stated in: § Abstract · plain
      “Here, by varying the linkers for CDK4/6-targeted degraders, we identified molecules capable of acutely and selectively degrading either CDK4 or CDK6.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ATP-binding pockets of CDK4 and CDK6 are highly conserved/homologous, and current CDK4/6 inhibitors are approximately equipotent for both proteins, making selective inhibition difficult.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CDK4/6 inhibitors are under investigation in subsets of lung cancers, sarcomas, and lymphomas such as mantle cell lymphoma (MCL), which exhibits aberrant cell cycle progression via activation of CDK4/6.

    “These agents are also currently under investigation in subsets of lung cancers, sarcomas, and lymphomas, such as mantle cell lymphoma (MCL), that exhibits aberrant cell cycle progression via activation of CDK4/6[3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Sherr CJ, Beach D, Shapiro GI, Cancer Discov 2016, 6, 353– 367. 26658964 PMC4821753 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The dual CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib are FDA-approved for treating patients with advanced or metastatic breast cancer and lead to prolonged progression-free survival.

    “As such, CDK4/6 are attractive targets for cancer therapy, and the dual CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib have been FDA approved for treating patients with advanced or metastatic breast cancer, leading to prolonged progression-free-survival[2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Laderian B, Fojo T, Semin Oncol 2017, 44, 395– 403. 29935901 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Selective degradation of CDK9 was achieved by converting the non-selective CDK inhibitor SNS-032 into a degrader.

    “For example, selective degradation of CDK9 was achieved by converting the non-selective CDK inhibitor SNS-032 into a degrader[9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Olson CM, Jiang B, Erb MA, Liang Y, Doctor ZM, Zhang Z, Zhang T, Kwiatkowski N, Boukhali M, Green JL, Haas W, Nomanbhoy T, Fischer ES, Young RA, Bradner JE, Winter GE, Gray NS, Nat Chem Biol 2018, 14, 163– 170. 29251720 PMC5912898 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Thalidomide binds to the E3 ligase substrate adapter Cereblon (CRBN) and has often been used as the E3 ligase-binding moiety in degraders.

    “The small molecule thalidomide, which binds to the ubiquitously expressed E3 ligase substrate adapter Cereblon (CRBN), has often been used as the E3 ligase-binding moiety in degraders[11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] a An S, Fu L, EBioMedicine 2018, 36, 553– 562; 30224312 PMC6197674 b Cromm PM, Crews CM, Cell Chem Biol 2017, 24, 1181– 1190. 28648379 PMC5610075 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CDK6 participates as part of a transcription complex that regulates expression of p16INK4a and VEGF-A.

    “On the other hand, CDK6-specific functions include participating as part of a transcription complex that regulates expression of p16INK4a and VEGF-A[5]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Kollmann K, Heller G, Schneckenleithner C, Warsch W, Scheicher R, Ott RG, Schafer M, Fajmann S, Schlederer M, Schiefer AI, Reichart U, Mayerhofer M, Hoeller C, Zochbauer-Muller S, Kerjaschki D, Bock C, Kenner L, Hoefler G, Freissmuth M, Green AR, Moriggl R, Busslinger M, Malumbres M, Sexl V, Cancer Cell 2013, 24, 167– 181. 23948297 PMC3743049 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CDK6 acts as a co-factor for NFκB-dependent gene expression.

    “and acting as a co-factor for NFκB-dependent gene expression[6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Handschick K, Beuerlein K, Jurida L, Bartkuhn M, Muller H, Soelch J, Weber A, Dittrich-Breiholz O, Schneider H, Scharfe M, Jarek M, Stellzig J, Schmitz ML, Kracht M, Molecular cell 2014, 53, 193– 208. 24389100 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These compounds may serve as selective probes for pharmacological dissection of the distinct CDK4 or CDK6 biological functions and as starting points for the development of therapeutic degrader molecules.

    “These compounds may serve as selective probes for pharmacological dissection of the distinct CDK4 or CDK6 biological functions and as starting points for the development of therapeutic degrader molecules.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ATP-binding pockets of CDK4 and CDK6 are highly conserved/homologous, and current CDK4/6 inhibitors are approximately equipotent for both proteins, making selective inhibition difficult.

  • May combine two claims.

    Premisecitation

    MCL is an incurable B cell non-Hodgkin lymphoma whose molecular hallmark is the t(11;14)(q13;q32) chromosomal translocation that juxtaposes CCND1 with the Ig heavy chain gene locus, resulting in aberrant cell cycle progression via activation of CDK4/6.

    “CDK4/6 inhibitors are currently being evaluated for MCL, an incurable B cell non-Hodgkin lymphoma whose molecular hallmark is the t(11;14)(q13;q32) chromosomal translocation that juxtaposes CCND1 (encoding cyclin D1) with the Ig heavy chain gene locus, resulting in aberrant cell cycle progression via activation of CDK4/6[17].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Jares P, Colomer D, Campo E, Nat Rev Cancer 2007, 7, 750– 762. 17891190 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CDK6, but not CDK4, phosphorylates NFAT family transcription factors to promote T cell activation and enhance the anti-tumor immune response.

    “We also recently demonstrated that CDK6, but not CDK4, phosphorylates NFAT family transcription factors to promote T cell activation and enhance the anti-tumor immune response[7].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates K, Chhabra S, Huang W, Liu H, Aref AR, Ivanova E, Paweletz CP, Bowden M, Zhou CW, Herter-Sprie GS, Sorrentino JA, Bisi JE, Lizotte PH, Merlino AA, Quinn MM, Bufe LE, Yang A, Zhang Y, Zhang H, Gao P, Chen T, Cavanaugh ME, Rode AJ, Haines E, Roberts PJ, Strum JC, Richards WG, Lorch JH, Parangi S, Gunda V, Boland GM, Bueno R, Palakurthi S, Freeman GJ, Ritz J, Haining WN, Sharpless NE, Arthanari H, Shapiro GI, Barbie DA, Gray NS, Wong KK, Cancer Discov 2018, 8, 216– 233. 29101163 PMC5809273 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    BSJ-02-162 (100 nM, 24 h) induced G1 arrest in wildtype but not Crbn−/− Jurkat cells, indicating that the cytostatic effect of CDK4/6 degraders required CRBN-dependent degradation of CDK4/6.

    “In contrast, treatment with 100 nM of BSJ-02–162 for 24h induced G1 arrest in wildtype but not Crbn−/− Jurkat cells, indicating that the cytostatic effect of CDK4/6 degraders required CRBN-dependent degradation of CDK4/6 (Figure 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premiseown data

    High-resolution crystal structures of palbociclib, ribociclib, and abemaciclib with CDK6 revealed similar binding modes where the aminopyrimidine moiety forms three hydrogen bonds with the backbones of Val101 and Asp163, and the piperazine ring is stabilized via direct interactions with a solvent-exposed ridge consisting of Asp104 and Thr107.

    “High-resolution crystal structures of palbociclib [PDB ID: 5L2I], ribociclib [PDB ID: 5L2T], and abemaciclib [PDB ID: 5L2S] with CDK6 revealed similar binding modes where the aminopyrimidine moiety forms three hydrogen bonds with the backbones of Val101 and Asp163, and the piperazine ring is stabilized via direct interactions with a solvent-exposed ridge consisting of Asp104 and Thr107.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites PDB ID: 5L2I

      Not checked in the free run.

    • cites PDB ID: 5L2T

      Not checked in the free run.

    • cites PDB ID: 5L2S

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The cellular effects of CDK4/6 degraders required the presence of CRBN and were dependent on target degradation rather than inhibition.

    “As these effects required the presence of CRBN, they were dependent on target degradation rather than inhibition.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Previous studies indicated that varying the thalidomide aryl amine nitrogen to an oxylamide could prevent recruitment of IKZF1/3 to CRBN.

    “As previous studies indicated that varying the thalidomide aryl amine nitrogen to an oxylamide could prevent recruitment of IKZF1/3 to CRBN[10, 13c]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10, 13c]

      Not checked in the free run.

20 of 20

  • The paper relies on this without support.

    The ATP-binding pockets of CDK4 and CDK6 are highly conserved/homologous, and current CDK4/6 inhibitors are approximately equipotent for both proteins, making selective inhibition difficult.

    “However, due to conservation of their ATP-binding sites, development of selective agents has remained elusive.”
    “As current CDK4/6 inhibitors target their highly conserved ATP-binding pockets and are approximately equipotent inhibitors of both proteins, we hypothesized that achieving selectivity would require exploiting selectivity determinants outside of the ATP-binding pocket.”
    “The highly homologous ATP-binding pockets of CDK4 and CDK6 has hindered the development of selective CDK4 or CDK6 probes.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Previous studies have shown that a nitrogen to oxygen modification on the thalidomide aryl attachment point can reduce or remove IMiD off-target effects in BTK and CDK4/6 targeted degraders.

    “Previous studies have shown that a nitrogen to oxygen modification on the thalidomide aryl attachment point can reduce or remove IMiD off-target effects in BTK and CDK4/6 targeted degraders (Dobrovolsky et al., 2019; Jiang et al., 2019).”

    From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Jiang 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 [74]

  • Some CRBN-based PROTACs have been shown to degrade the natural substrates of CRBN such as IKZF1 and IKZF3.

    “some CRBN-based PROTACs have been shown to degrade the natural substrates of CRBN such as IKZF1 and IKZF3 [86, 87].”

    From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [87]

  • Some CRBN-recruiting PROTACs have been shown to catalyse the degradation of the IMiD targets IKZF1 and IKZF3.

    “and some CRBNrecruiting PROTACs have been shown to catalyse the degradation of the IMiD targets IKFZ1 and IKFZ3 (refs 40,41 ).”

    From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [41]

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Related

Authors
Jiang, B., Wang, E. S., Donovan, K. A., Liang, Y., Fischer, E. S., Zhang, T., & Gray, N. S.
Affiliations
Dana-Farber Cancer Institute (US)
Corresponding author
  • Zhang, Tinghu
  • Gray, Nathanael S.
ORCID
Venue
Angewandte Chemie International Edition
Publisher
Wiley
Published
2019-03-29
Volume
58
Issue
19
Pages
6321-6326
ISSN
  • 1433-7851 (ISSN-L)
  • 1521-3773
DOI
10.1002/anie.201901336
PMC
PMC7678623
OpenAlex
W2917565897
Semantic Scholar
453a25d8c1f9a6987f549b2e132dc50d712ec85d
Cited by
272
References
24
Citations by year
2026: 19 · 2025: 46 · 2024: 39 · 2023: 26 · 2022: 38 · 2021: 47 · 2020: 43 · 2019: 14
FWCI
12.49
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Angewandte Chemie International Edition (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Damon Runyon Cancer Research Foundation (DRG-2270-16, DRR-50-18)
  • National Institutes of Health (R01CA218278)
  • Dana-Farber Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
Keywords
CDK4, CDK6, selective degradation, mantle cell lymphoma, metastatic breast cancer, cell cycle regulation, antiproliferative activity
MeSH terms
Humans, Imides, Piperazines, Pyridines, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Ikaros Transcription Factor, Cell Cycle Checkpoints

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