CDK4 inhibitor

CDK4/Cyclin D1 inhibitor CAS# 1256963-02-6

CDK4 inhibitor

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Chemical structure

CDK4 inhibitor

3D structure

Chemical Properties of CDK4 inhibitor

Cas No. 1256963-02-6 SDF Download SDF
PubChem ID 49765254 Appearance Powder
Formula C22H29ClN8 M.Wt 440.97
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble in DMSO
Chemical Name 4-(3-chloro-5-propan-2-yl-1H-pyrazol-4-yl)-N-[5-[4-(dimethylamino)piperidin-1-yl]pyridin-2-yl]pyrimidin-2-amine
SMILES CC(C)C1=C(C(=NN1)Cl)C2=NC(=NC=C2)NC3=NC=C(C=C3)N4CCC(CC4)N(C)C
Standard InChIKey JKFGTURSEBTJIZ-UHFFFAOYSA-N
Standard InChI InChI=1S/C22H29ClN8/c1-14(2)20-19(21(23)29-28-20)17-7-10-24-22(26-17)27-18-6-5-16(13-25-18)31-11-8-15(9-12-31)30(3)4/h5-7,10,13-15H,8-9,11-12H2,1-4H3,(H,28,29)(H,24,25,26,27)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

CDK4 inhibitor Dilution Calculator

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CDK4 inhibitor Molarity Calculator

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Preparing Stock Solutions of CDK4 inhibitor

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.2677 mL 11.3386 mL 22.6773 mL 45.3546 mL 56.6932 mL
5 mM 0.4535 mL 2.2677 mL 4.5355 mL 9.0709 mL 11.3386 mL
10 mM 0.2268 mL 1.1339 mL 2.2677 mL 4.5355 mL 5.6693 mL
50 mM 0.0454 mL 0.2268 mL 0.4535 mL 0.9071 mL 1.1339 mL
100 mM 0.0227 mL 0.1134 mL 0.2268 mL 0.4535 mL 0.5669 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on CDK4 inhibitor

CDK4 inhibitor is a selective inhibitor of cyclin-dependent kinase 4 with IC50 value of 10 nM [1].

Cyclin-dependent kinase 4 (CDK4) is a Ser/Thr protein kinase and is a member of the cyclin-dependent kinase family. CDK4 plays an important role in the G1-S phase.

CDK4 inhibitor is a selective cyclin-dependent kinase 4 inhibitor. CDK4 inhibitor inhibited CDK4/Cyclin D1, CDK1/Cyclin B and CDK2/Cyclin A with IC50 values of 10 nM, 15 μM and 5.265 μM, respectively. Also, it inhibited protein kinase A (PKA) and glycogen synthase kinase (GSK3β) with IC50 values of 6.8 and 9.6 μM, respectively. In a mantle-cell lymphoma cell line Jeko-1, CDK4 inhibitor inhibited the phosphorylation level of pRb at the Ser780 site with IC50 value of 0.324 μM. Also, CDK4 inhibitor (0.37 μM) showed G1 block on cells [1].

Reference:
[1].  Cho YS, Borland M, Brain C, et al. 4-(Pyrazol-4-yl)-pyrimidines as selective inhibitors of cyclin-dependent kinase 4/6. J Med Chem, 2010, 53(22): 7938-7957.

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References on CDK4 inhibitor

Molecular mechanism of G1 arrest and cellular senescence induced by LEE011, a novel CDK4/CDK6 inhibitor, in leukemia cells.[Pubmed:28286417]

Cancer Cell Int. 2017 Mar 6;17:35.

BACKGROUND: Overexpression of cyclin D1 dependent kinases 4 and 6 (CDK4/6) is a common feature of many human cancers including leukemia. LEE011 is a novel inhibitor of both CDK4 and 6. To date, the molecular function of LEE011 in leukemia remains unclear. METHODS: Leukemia cell growth and apoptosis following LEE011 treatment was assessed through CCK-8 and annexin V/propidium iodide staining assays. Cell senescence was assessed by beta-galactosidase staining and p16(INK4a) expression analysis. Gene expression profiles of LEE011 treated HL-60 cells were investigated using an Arraystar Human LncRNA array. Gene ontology and KEGG pathway analysis were then used to analyze the differentially expressed genes from the cluster analysis. RESULTS: Our studies demonstrated that LEE011 inhibited proliferation of leukemia cells and could induce apoptosis. Hoechst 33,342 staining analysis showed DNA fragmentation and distortion of nuclear structures following LEE011 treatment. Cell cycle analysis showed LEE011 significantly induced cell cycle G1 arrest in seven of eight acute leukemia cells lines, the exception being THP-1 cells. beta-Galactosidase staining analysis and p16(INK4a) expression analysis showed that LEE011 treatment can induce cell senescence of leukemia cells. LncRNA microarray analysis showed 2083 differentially expressed mRNAs and 3224 differentially expressed lncRNAs in LEE011-treated HL-60 cells compared with controls. Molecular function analysis showed that LEE011 induced senescence in leukemia cells partially through downregulation of the transcriptional expression of MYBL2. CONCLUSIONS: We demonstrate for the first time that LEE011 treatment results in inhibition of cell proliferation and induction of G1 arrest and cellular senescence in leukemia cells. LncRNA microarray analysis showed differentially expressed mRNAs and lncRNAs in LEE011-treated HL-60 cells and we demonstrated that LEE011 induces cellular senescence partially through downregulation of the expression of MYBL2. These results may open new lines of investigation regarding the molecular mechanism of LEE011 induced cellular senescence.

Targeting cancer stem cell propagation with palbociclib, a CDK4/6 inhibitor: Telomerase drives tumor cell heterogeneity.[Pubmed:28039467]

Oncotarget. 2017 Feb 7;8(6):9868-9884.

In this report, we systematically examined the role of telomerase activity in lung and ovarian cancer stem cell (CSC) propagation. For this purpose, we indirectly gauged telomerase activity, by linking the hTERT-promoter to eGFP. Using lung (A549) and ovarian (SKOV3) cancer cells, transduced with the hTERT-GFP reporter, we then employed GFP-expression levels to fractionate these cell lines into GFP-high and GFP-low populations. We functionally compared the phenotype of these GFP-high and GFP-low populations. More specifically, we now show that the cancer cells with higher telomerase activity (GFP-high) are more energetically activated, with increased mitochondrial mass and function, as well as increased glycolytic activity. This was further validated and confirmed by unbiased proteomics analysis. Cells with high telomerase activity also showed an increased capacity for stem cell activity (as measured using the 3D-spheroid assay) and cell migration (as measured using a Boyden chamber approach). These enhanced biological phenotypes were effectively inhibited by classical modulators of energy metabolism, which target either i) mitochondrial metabolism (i.e., oligomycin) or ii) glycolysis (i.e., 2-deoxy-glucose), or iii) by using the FDA-approved antibiotic doxycycline, which inhibits mitochondrial biogenesis. Finally, the level of telomerase activity also determined the ability of hTERT-high cells to proliferate, as assessed by measuring DNA synthesis via EdU incorporation. Consistent with these observations, treatment with an FDA-approved CDK4/6 inhibitor (PD-0332991/palbociclib) specifically blocked the propagation of both lung and ovarian CSCs. Virtually identical results were obtained with breast CSCs, which were also highly sensitive to palbociclib at concentrations in the nanomolar range. In summary, CSCs with high telomerase activity are among the most energetically activated, migratory and proliferative cell sub-populations. These observations may provide a mechanistic explanation for tumor metabolic heterogeneity, based on telomerase activity. FDA-approved drugs, such as doxycycline and palbociclib, were both effective at curtailing CSC propagation. Thus, these FDA-approved drugs could be used to target telomerase-high proliferative CSCs, in multiple cancer types. Finally, our experiments also allowed us to distinguish two different cellular populations of hTERT-high cells, one that was proliferative (i.e., replicative immortality) and the other that was non-proliferative (i.e., quiescent). We speculate that the non-proliferative population of hTERT-high cells that we identified could be mechanistically involved in tumor dormancy.

Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia.[Pubmed:28151717]

Clin Cancer Res. 2017 Feb 15;23(4):1012-1024.

Purpose: Although significant progress has been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), many patients will require additional therapy for relapsed/refractory disease. Cyclin D3 (CCND3) and CDK6 are highly expressed in T-ALL and have been effectively targeted in mutant NOTCH1-driven mouse models of this disease with a CDK4/6 small-molecule inhibitor. Combination therapy, however, will be needed for the successful treatment of human disease.Experimental Design: We performed preclinical drug testing using a panel of T-ALL cell lines first with LEE011, a CDK4/6 inhibitor, and next with the combination of LEE011 with a panel of drugs relevant to T-ALL treatment. We then tested the combination of LEE011 with dexamethasone or everolimus in three orthotopic mouse models and measured on-target drug activity.Results: We first determined that both NOTCH1-mutant and wild-type T-ALL are highly sensitive to pharmacologic inhibition of CDK4/6 when wild-type RB is expressed. Next, we determined that CDK4/6 inhibitors are antagonistic when used either concurrently or in sequence with many of the drugs used to treat relapsed T-ALL (methotrexate, mercaptopurine, asparaginase, and doxorubicin) but are synergistic with glucocorticoids, an mTOR inhibitor, and gamma secretase inhibitor. The combinations of LEE011 with the glucocorticoid dexamethasone or the mTOR inhibitor everolimus were tested in vivo and prolonged survival in three orthotopic mouse models of T-ALL. On-target activity was measured in peripheral blood and tissue of treated mice.Conclusions: We conclude that LEE011 is active in T-ALL and that combination therapy with corticosteroids and/or mTOR inhibitors warrants further investigation. Clin Cancer Res; 23(4); 1012-24. (c)2016 AACRSee related commentary by Carroll et al., p. 873.

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