Top ▲

cyclin dependent kinase 6

Click here for help

Target id: 1978

Nomenclature: cyclin dependent kinase 6

Abbreviated Name: CDK6

Family: CDK4 subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 326 7q21.2 CDK6 cyclin dependent kinase 6
Mouse - 326 5 2.04 cM Cdk6 cyclin dependent kinase 6
Rat - 326 4 q13 Cdk6 cyclin-dependent kinase 6
Previous and Unofficial Names Click here for help
CR2 protein kinase | CRK2 | Serine/threonine-protein kinase PLSTIRE
Database Links Click here for help
Alphafold Q00534 (Hs), Q64261 (Mm)
BRENDA 2.7.11.22
ChEMBL Target CHEMBL2508 (Hs)
Ensembl Gene ENSG00000105810 (Hs), ENSMUSG00000040274 (Mm), ENSRNOG00000009258 (Rn)
Entrez Gene 1021 (Hs), 12571 (Mm), 114483 (Rn)
Human Protein Atlas ENSG00000105810 (Hs)
KEGG Enzyme 2.7.11.22
KEGG Gene hsa:1021 (Hs), mmu:12571 (Mm), rno:114483 (Rn)
OMIM 603368 (Hs)
Orphanet ORPHA377025 (Hs)
Pharos Q00534 (Hs)
RefSeq Nucleotide NM_001145306 (Hs), NM_009873 (Mm), NM_001191861 (Rn)
RefSeq Protein NP_001138778 (Hs), NP_034003 (Mm), NP_001178790 (Rn)
SynPHARM 79368 (in complex with palbociclib)
UniProtKB Q00534 (Hs), Q64261 (Mm)
Wikipedia CDK6 (Hs)
Selected 3D Structures Click here for help
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:  6
Enzyme Reaction Click here for help
EC Number: 2.7.11.22

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PF-06873600 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 10.1 pKi 2
⤷ pKi 10.1 (Ki 8x10-11 M) [2]
Description: Evaluated in a CDK6/Cyclin D1 mobility shift assay.
ulecaciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.8 pKi 24
⤷ pKi 7.8 (Ki 1.4x10-8 M) [24]
Description: Inhibition of CDK6/cyclin D3 in vitro
crozbaciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.0 pIC50 26
⤷ pIC50 9.0 (IC50 1x10-9 M) [26]
Description: Inhibition of CDK6/cyclin D3 in vitro
inixaciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.0 pIC50 17
⤷ pIC50 9.0 (IC50 1x10-9 M) [17]
trilaciclib Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.4 pIC50 3
⤷ pIC50 8.4 (IC50 4x10-9 M) [3]
Description: Inhibition of CDK6/cyclin D3
lerociclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.3 pIC50 21
⤷ pIC50 8.3 (IC50 4.7x10-9 M) [21]
Description: Inhibition of CDK6/cyclin D3 complex
dalpiciclib Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 8.2 pIC50 23
⤷ pIC50 8.2 (IC50 6x10-9 M) [23]
cimpuciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.0 pIC50 14
⤷ pIC50 8.0 (IC50 9.56x10-9 M) [14]
narazaciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.0 pIC50 19
⤷ pIC50 8.0 (IC50 9.82x10-9 M) [19]
Description: CDK6/CyclinD1
abemaciclib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pIC50 11
⤷ pIC50 8.0 (IC50 1x10-8 M) [11]
Description: CDK6/cyclin D1 complex expressed in and purified from insect cells. Assays used the methanesulfonate salt of the compound.
BSJ-03-204 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.0 pIC50 13
⤷ pIC50 8.0 (IC50 1.04x10-8 M) [13]
Description: Inhibition of CDK6/cyclin D1 kinase activity in a biochemical assay.
palbociclib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 – 8.0 pIC50 9,22-23
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [22]
pIC50 7.8 (IC50 1.6x10-8 M) [9]
pIC50 7.4 (IC50 3.6x10-8 M) [23]
tibremciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.7 pIC50 25
⤷ pIC50 7.7 (IC50 2.2x10-8 M) [25]
BSJ-04-132 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.5 pIC50 13
⤷ pIC50 7.5 (IC50 3x10-8 M) [13]
Description: Inhibition of CDK6/cyclin D1 kinase activity in a biochemical assay.
tanuxiciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.5 pIC50 5
⤷ pIC50 7.5 (IC50 3.38x10-8 M) [5]
Description: CDK6/cyclinD
BSJ-03-123 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 13
⤷ pIC50 7.4 (IC50 3.77x10-8 M) [13]
Description: Inhibition of CDK6/cyclin D1 activity in a biochemical kinase assay.
RGB-286638 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.3 pIC50 7
⤷ pIC50 7.3 (IC50 5.5x10-8 M) [7]
Description: in association with cyclin D3
AT-7519 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.8 pIC50 20
⤷ pIC50 6.8 (IC50 1.7x10-7 M) [20]
voruciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.7 pIC50 15
⤷ pIC50 6.7 (IC50 2.1x10-7 M) [15]
Description: Inhibition of CDK6/cyclinD3.
CP-10 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.6 pIC50 22
⤷ pIC50 6.6 (IC50 2.62x10-7 M) [22]
Cdk/Crk inhibitor Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.6 pIC50 8
⤷ pIC50 6.6 (IC50 2.82x10-7 M) [8]
Description: CDK6/cyclin D3 complex
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
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: 1,10
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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.0 40.5 8.5
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.3 10.0 4.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.9 19.0 3.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 5.8 15.0 4.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 6.1 95.0 76.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 6.3 22.0 6.0
alsterpaullone 2-cyanoethyl Small molecule or natural product Hs Inhibitor Inhibition 6.8 30.0 8.0
Cdk4 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 12.2 87.0 58.0
SU9516 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 13.3 51.0 9.0
alsterpaullone Small molecule or natural product Ligand has a PDB structure 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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 4.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 7.2
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.7
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 9.9
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 10.2
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 11.7
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 12.2
dorsomorphin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 14.8
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 19.9
Flt-3 inhibitor III Small molecule or natural product 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 [12,16]. 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 [18].
Immuno Process Associations
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  T cell (activation)
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
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

Show »

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. Changhee M, Oh B-g, Kim Y-e, Park C-m. (2016) Heterocyclic compound and pharmaceutical composition comprising same. Patent number: WO2016126085A2. Assignee: Beyond Bio. Priority date: 04/02/2015. Publication date: 03/11/2016.

6. 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]

7. 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]

8. 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 USA, 104 (51): 20523-8. [PMID:18077363]

9. 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]

10. 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]

11. 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]

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

13. Jiang B, Wang ES, Donovan KA, Liang Y, Fischer ES, Zhang T, Gray NS. (2019) Development of Dual and Selective Degraders of Cyclin-Dependent Kinases 4 and 6. Angew Chem Int Ed Engl, 58 (19): 6321-6326. [PMID:30802347]

14. Liu S, Zhou Y, Wu X, Bao R. (2018) Benzimidazole compound kinase inhibitor, preparation method therefor and application thereof. Patent number: WO2018045956A1. Assignee: Jiangsu Haosen Pharmaceutical Group, Shanghai Hansen Biomedical Technology Co.. Priority date: 07/09/2016. Publication date: 15/03/2018.

15. 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]

16. 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]

17. Pham SM, Chakravarty S, Kanlanala J, Pujala B, Shete A, Bhatt B, Agarwal AK, Soni S, Chen J. (2019) Heterocyclic compounds as kinase inhibitors. Patent number: WO2019161224A1. Assignee: GiraFpharma LLC. Priority date: 15/02/2018. Publication date: 22/08/2019.

18. 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]

19. Reddy MV, Akula B, Cosenza SC, Athuluridivakar S, Mallireddigari MR, Pallela VR, Billa VK, Subbaiah DR, Bharathi EV, Vasquez-Del Carpio R et al.. (2014) Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5). J Med Chem, 57 (3): 578-99. [PMID:24417566]

20. 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]

21. 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.

22. Su S, Yang Z, Gao H, Yang H, Zhu S, An Z, Wang J, Li Q, Chandarlapaty S, Deng H et al.. (2019) Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders. J Med Chem, 62 (16): 7575-7582. [PMID:31330105]

23. Sun P, Lan J, Peng J, Chen Y, Wang B, Dong Q. (2014) Thiophene miazines derivate, preparation method therefor, and medical application thereof. Patent number: WO2014183520A1. Assignee: Shanghai Hengrui Pharmaceutical Co. Priority date: 17/05/2013. Publication date: 20/11/2014.

24. Tadesse S, Yu M, Mekonnen LB, Lam F, Islam S, Tomusange K, Rahaman MH, Noll B, Basnet SK, Teo T et al.. (2017) Highly Potent, Selective, and Orally Bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation. J Med Chem, 60 (5): 1892-1915. [PMID:28156111]

25. Wang Y, Zhang C, Wang J, Ding L. (2021) Crystal form of compound for inhibiting the activity of cdk4/6 and use thereof. Patent number: US20210261546A1. Assignee: Betta Pharmaceuticals Co Ltd. Priority date: 21/06/2019. Publication date: 26/08/2021.

26. Yin L, Li H, Liu W, Yao Z, Cheng Z, Zhang H, Zou H. (2018) A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy. Eur J Med Chem, 144: 1-28. [PMID:29247857]

How to cite this page

CDK4 subfamily: cyclin dependent kinase 6. Last modified on 14/08/2023. Accessed on 24/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1978.