cyclin dependent kinase 6 | CDK4 subfamily | IUPHAR Guide to IMMUNOPHARMACOLOGY

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cyclin dependent kinase 6

  Target has curated data in GtoImmuPdb

Target id: 1978

Nomenclature: cyclin dependent kinase 6

Abbreviated Name: CDK6

Family: CDK4 subfamily

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 326 7q21-q22 CDK6 cyclin dependent kinase 6
Mouse - 326 5 A2-A3 Cdk6 cyclin-dependent kinase 6
Rat - 326 4 q13 Cdk6 cyclin-dependent kinase 6
Previous and Unofficial Names
CR2 protein kinase | CRK2 | Serine/threonine-protein kinase PLSTIRE
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human CLK1 in complex with 10Z-Hymenialdisine
PDB Id:  1Z57
Resolution:  1.7Å
Species:  Human
References:  4
Image of receptor 3D structure from RCSB PDB
Description:  Liganded X-ray crystal structure of cyclin dependent kinase 6 (CDK6)
PDB Id:  4AUA
Resolution:  2.31Å
Species:  Human
References:  5
Enzyme Reaction
EC Number: 2.7.11.22

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
example 10 [WO2018033815] Hs Inhibition 10.1 pKi 2
pKi 10.1 (Ki 8x10-11 M) [2]
Description: Evaluated in a CDK6/Cyclin D1 mobility shift assay.
trilaciclib Hs Inhibition 8.4 pIC50 3
pIC50 8.4 (IC50 4x10-9 M) [3]
Description: Inhibition of CDK6/cyclin D3
G1T38 Hs Inhibition 8.3 pIC50 16
pIC50 8.3 (IC50 4.7x10-9 M) [16]
Description: Inhibition of CDK6/cyclin D3 complex
abemaciclib Hs Inhibition 8.0 pIC50 10
pIC50 8.0 (IC50 1x10-8 M) [10]
Description: CDK6/cyclin D1 complex expressed in and purified from insect cells. Assays used the methanesulfonate salt of the compound.
palbociclib Hs Inhibition 7.8 pIC50 8
pIC50 7.8 (IC50 1.6x10-8 M) [8]
RGB-286638 Hs Inhibition 7.3 pIC50 6
pIC50 7.3 (IC50 5.5x10-8 M) [6]
Description: in association with cyclin D3
AT-7519 Hs Inhibition 6.8 pIC50 15
pIC50 6.8 (IC50 1.7x10-7 M) [15]
voruciclib Hs Inhibition 6.7 pIC50 12
pIC50 6.7 (IC50 2.1x10-7 M) [12]
Description: Inhibition of CDK6/cyclinD3.
Cdk/Crk inhibitor Hs Inhibition 6.6 pIC50 7
pIC50 6.6 (IC50 2.82x10-7 M) [7]
Description: CDK6/cyclin D3 complex
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 1,9

Key to terms and symbols Click column headers to sort
Target used in screen: CDK6-cyclin D3/CDK6-cyclin D1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 1.0 40.5 8.5
PKR inhibitor Hs Inhibitor Inhibition 2.3 10.0 4.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 2.9 19.0 3.0
K-252a Hs Inhibitor Inhibition 5.8 15.0 4.0
SB 218078 Hs Inhibitor Inhibition 6.1 95.0 76.0
JAK3 inhibitor VI Hs Inhibitor Inhibition 6.3 22.0 6.0
alsterpaullone 2-cyanoethyl Hs Inhibitor Inhibition 6.8 30.0 8.0
Cdk4 inhibitor Hs Inhibitor Inhibition 12.2 87.0 58.0
SU9516 Hs Inhibitor Inhibition 13.3 51.0 9.0
alsterpaullone Hs Inhibitor Inhibition 16.8 60.0 26.0
Target used in screen: nd/CDK6-cyclin D3
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
PKR inhibitor Hs Inhibitor Inhibition 4.0
K-252a Hs Inhibitor Inhibition 7.2
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 7.7
PDK1/Akt/Flt dual pathway inhibitor Hs Inhibitor Inhibition 9.9
indirubin derivative E804 Hs Inhibitor Inhibition 10.2
staurosporine Hs Inhibitor Inhibition 11.7
JAK3 inhibitor VI Hs Inhibitor Inhibition 12.2
dorsomorphin Hs Inhibitor Inhibition 14.8
SB 218078 Hs Inhibitor Inhibition 19.9
Flt-3 inhibitor III Hs Inhibitor Inhibition 20.1
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
Phenotypic abnormalities in CDK6 knockout mice suggest biological roles in addition to mitotic cell cycle regulation. Alternate roles include involvement in hematopoietic function and inhibition of T cell differentiation [11,13]. The T cell differentiation function is not shared by CDK4. In mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML) depletion of CDK6 (either by shRNA knockdown or using the approved small molecule CDK4/6 inhibitor palbociclib) causes growth inhibition and differentiation of MLL-driven leukemic cells [14].
Immuno Process Associations
Immuno Process:  Immune regulation
GO Annotations:  Associated to 4 GO processes
GO:0045638 negative regulation of myeloid cell differentiation IDA
GO:0045646 regulation of erythrocyte differentiation IMP
GO:0045656 negative regulation of monocyte differentiation IDA
click arrow to show/hide IEA associations
GO:1902036 regulation of hematopoietic stem cell differentiation IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 6 GO processes
GO:0045638 negative regulation of myeloid cell differentiation IDA
GO:0045646 regulation of erythrocyte differentiation IMP
GO:0045656 negative regulation of monocyte differentiation IDA
click arrow to show/hide IEA associations
GO:0033077 T cell differentiation in thymus IEA
GO:0060218 hematopoietic stem cell differentiation IEA
GO:1902036 regulation of hematopoietic stem cell differentiation IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0033077 T cell differentiation in thymus IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0033077 T cell differentiation in thymus IEA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Microcephaly 12, primary, autosomal recessive; MCPH12
Synonyms: Autosomal recessive primary microcephaly [Orphanet: ORPHA2512]
OMIM: 616080
Orphanet: ORPHA2512
Biologically Significant Variant Comments
Single nucleotide polymorphisms in the CDK6 gene are associated with variation in adult human height. For more details see the OMIM entry 612223.

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

2. Behenna DC, Chen P, Freeman-Cook KD, Hoffman RL, Jalaie M, Nagata A, Nair SK, Ninkovic S, Ornelas MA, Palmer CL et al.. (2018) Pyridopyrimdinone cdk2/4/6 inhibitors. Patent number: WO2018033815A1. Assignee: Pfizer Inc.. Priority date: 15/08/2016. Publication date: 22/02/2018.

3. Bisi JE, Sorrentino JA, Roberts PJ, Tavares FX, Strum JC. (2016) Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression. Mol. Cancer Ther., 15 (5): 783-93. [PMID:26826116]

4. Bullock AN, Das S, Debreczeni JE, Rellos P, Fedorov O, Niesen FH, Guo K, Papagrigoriou E, Amos AL, Cho S et al.. (2009) Kinase domain insertions define distinct roles of CLK kinases in SR protein phosphorylation. Structure, 17 (3): 352-62. [PMID:19278650]

5. Cho YS, Angove H, Brain C, Chen CH, Cheng H, Cheng R, Chopra R, Chung K, Congreve M, Dagostin C et al.. (2012) Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors. ACS Med Chem Lett, 3 (6): 445-9. [PMID:24900493]

6. Cirstea D, Hideshima T, Santo L, Eda H, Mishima Y, Nemani N, Hu Y, Mimura N, Cottini F, Gorgun G et al.. (2013) Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia, 27 (12): 2366-75. [PMID:23807770]

7. Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc. Natl. Acad. Sci. U.S.A., 104 (51): 20523-8. [PMID:18077363]

8. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK et al.. (2004) Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol. Cancer Ther., 3 (11): 1427-38. [PMID:15542782]

9. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

10. Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ, Torres R, Ajamie RT, Wishart GN, Flack RS et al.. (2014) Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs, 32 (5): 825-37. [PMID:24919854]

11. Grossel MJ, Hinds PW. (2006) From cell cycle to differentiation: an expanding role for cdk6. Cell Cycle, 5 (3): 266-70. [PMID:16410727]

12. Paiva C, Godbersen JC, Soderquist RS, Rowland T, Kilmarx S, Spurgeon SE, Brown JR, Srinivasa SP, Danilov AV. (2015) Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells. PLoS ONE, 10 (11): e0143685. [PMID:26606677]

13. Patel SP, Randle SJ, Gibbs S, Cooke A, Laman H. (2017) Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27. Cell. Mol. Life Sci., 74 (8): 1553-1566. [PMID:27915416]

14. Placke T, Faber K, Nonami A, Putwain SL, Salih HR, Heidel FH, Krämer A, Root DE, Barbie DA, Krivtsov AV et al.. (2014) Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood, 124 (1): 13-23. [PMID:24764564]

15. Squires MS, Feltell RE, Wallis NG, Lewis EJ, Smith DM, Cross DM, Lyons JF, Thompson NT. (2009) Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol. Cancer Ther., 8 (2): 324-32. [PMID:19174555]

16. Strum JC, Bisi JE, Roberts PJ, Tavares FX. (2016) Transient protection of normal cells during chemotherapy. Patent number: US9464092B2. Assignee: G1 Therapeutics Inc. Priority date: 15/03/2013. Publication date: 11/10/2016.

How to cite this page

CDK4 subfamily: cyclin dependent kinase 6. Last modified on 10/07/2019. Accessed on 17/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1978.