cyclin dependent kinase 4 | CDK4 subfamily | IUPHAR/BPS Guide to PHARMACOLOGY

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cyclin dependent kinase 4

Target not currently curated in GtoImmuPdb

Target id: 1976

Nomenclature: cyclin dependent kinase 4

Abbreviated Name: CDK4

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 - 303 12q14 CDK4 cyclin dependent kinase 4
Mouse - 303 10 D3 Cdk4 cyclin-dependent kinase 4
Rat - 303 7q22 Cdk4 cyclin-dependent kinase 4
Previous and Unofficial Names
cell division protein kinase 4 | CRK3 | p34/cdk4 | PSK-J3
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  CRYSTAL STRUCTURE OF CDK4 IN COMPLEX WITH A D-TYPE CYCLIN
PDB Id:  2W96
Resolution:  2.3Å
Species:  Human
References:  9
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
trilaciclib Hs Inhibition 10.0 pKd 3
pKd 10.0 (Kd 1x10-10 M) [3]
Description: Inhibition of CDK4/cyclin D3
R547 Hs Inhibition 9.0 pKi 10
pKi 9.0 (Ki 1x10-9 M) [10]
Description: Assayed using CDK4/cyclin D1 complex.
example 10 [WO2018033815] Hs Inhibition 8.9 pKi 2
pKi 8.9 (Ki 1.37x10-9 M) [2]
Description: Evaluated in a CDK4/Cyclin D3 mobility shift assay.
alvocidib Hs Inhibition 7.2 pKi 6
pKi 7.2 (Ki 6.5x10-8 M) [6]
BMS-387032 Hs Inhibition 6.0 pKi 15
pKi 6.0 (Ki 9.25x10-7 M) [15]
trilaciclib Hs Inhibition 9.0 pIC50 3
pIC50 9.0 (IC50 1x10-9 M) [3]
Description: Inhibition of CDK4/cyclin D1
G1T38 Hs Inhibition 9.0 pIC50 28
pIC50 9.0 (IC50 1x10-9 M) [28]
Description: Inhibition of CDK4/cyclin D1
abemaciclib Hs Inhibition 8.7 pIC50 13
pIC50 8.7 (IC50 2x10-9 M) [13]
Description: CDK4/cyclin D1 complex expressed in and purified from insect cells. Assays used the methanesulfonate salt of the compound.
RGB-286638 Hs Inhibition 8.4 pIC50 7
pIC50 8.4 (IC50 4x10-9 M) [7]
Description: in association with cyclin D1
Cdk4 inhibitor III Hs Inhibition 8.2 pIC50 25
pIC50 8.2 (IC50 6x10-9 M) [25]
Description: CDK4/cyclin D1 complex
ribociclib Hs Inhibition 8.0 pIC50 4
pIC50 8.0 (IC50 1x10-8 M) [4]
palbociclib Hs Inhibition 8.0 pIC50 12
pIC50 8.0 (IC50 1.1x10-8 M) [12]
Ro-0505124 Hs Inhibition 7.7 pIC50 11
pIC50 7.7 (IC50 2x10-8 M) [11]
BSJ-03-204 Hs Inhibition 7.6 pIC50 16
pIC50 7.6 (IC50 2.69x10-8 M) [16]
Description: Inhibition of CDK4/cyclin D1 kinase activity in a biochemical assay.
compound 9b [PMID: 18986805] Hs Inhibition 7.3 pIC50 17
pIC50 7.3 (IC50 5x10-8 M) [17]
BSJ-04-132 Hs Inhibition 7.3 pIC50 16
pIC50 7.3 (IC50 5.06x10-8 M) [16]
Description: Inhibition of CDK4/cyclin D1 kinase activity in a biochemical assay.
riviciclib Hs Inhibition 7.2 pIC50 20
pIC50 7.2 (IC50 6.3x10-8 M) [20]
Description: CDK4/cyclin D1 complex
Cdk4 inhibitor Hs Inhibition 7.1 pIC50 30
pIC50 7.1 (IC50 7.6x10-8 M) [30]
Description: CDK4/cyclin D1 complex
voruciclib Hs Inhibition 7.1 pIC50 23
pIC50 7.1 (IC50 9x10-8 M) [23]
Description: Inhibition of CDK4/cyclinD1.
AT-7519 Hs Inhibition 7.0 pIC50 27
pIC50 7.0 (IC50 1x10-7 M) [27]
BSJ-03-123 Hs Inhibition 7.0 pIC50 16
pIC50 7.0 (IC50 1.06x10-7 M) [16]
Description: Inhibition of CDK4/cyclin D1 activity in a biochemical kinase assay.
milciclib Hs Inhibition 6.7 – 6.8 pIC50 5,19
pIC50 6.8 (IC50 1.6x10-7 M) [5]
Description: CDK4/cyclin D1 complex
pIC50 6.7 (IC50 2.2x10-7 M) [19]
Description: In vitro inhibition of CDK4/cyclin D.
Cdk4 inhibitor II Hs Inhibition 6.7 pIC50 21
pIC50 6.7 (IC50 2x10-7 M) [21]
Description: CDK4/cyclin D1 complex used in assay
fascaplysin Hs Inhibition 6.5 pIC50 26
pIC50 6.5 (IC50 3.5x10-7 M) [26]
Description: CDK4/cyclin D1 complex
SU9516 Hs Inhibition 5.8 – 6.7 pIC50 19,22
pIC50 6.7 (IC50 2x10-7 M) [22]
Description: CDK4/cyclin D1 complex used in assay
pIC50 5.8 (IC50 1.7x10-6 M) [19]
Description: In vitro inhibition of CDK4/cyclin D.
CDK inhibitor 4.35 Hs Inhibition 6.2 pIC50 18
pIC50 6.2 (IC50 6.03x10-7 M) [18]
Description: Inhibition of CDK4/cyclin D1 complex.
purvalanol A Hs Inhibition 6.1 pIC50 14
pIC50 6.1 (IC50 8.5x10-7 M) [14]
Description: CDK4/cyclin D1 complex used in assay
CGP74514A Hs Inhibition 5.5 pIC50 19
pIC50 5.5 (IC50 3x10-6 M) [19]
Description: In vitro inhibition of human CDK4/cyclin D.
Cdk2 inhibitor IV Hs Inhibition 5.3 pIC50 24
pIC50 5.3 (IC50 5.5x10-6 M) [24]
Description: CDK4/cyclin D complex used in assay
purvalanol B Hs Inhibition <5.0 pIC50 14
pIC50 <5.0 (IC50 >1x10-5 M) [14]
Description: CDK4/cyclin D1 complex used in assay
Inhibitor Comments
Fascaplysin did not inhibit CDK4/cyclin D2 and CDK4/cyclin D3 at concentrations >100μM, but did inhibit CDK6/cyclin D2 but with a low affinity of 35000nM [26].
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 8,29

Key to terms and symbols Click column headers to sort
Target used in screen: CDK4-cyclinD1
Ligand Sp. Type Action Value Parameter
R547 Hs Inhibitor Inhibition 9.2 pKd
alvocidib Hs Inhibitor Inhibition 8.1 pKd
AT-7519 Hs Inhibitor Inhibition 7.7 pKd
lestaurtinib Hs Inhibitor Inhibition 7.5 pKd
staurosporine Hs Inhibitor Inhibition 7.3 pKd
BMS-387032 Hs Inhibitor Inhibition 7.2 pKd
ruboxistaurin Hs Inhibitor Inhibition 6.6 pKd
KW-2449 Hs Inhibitor Inhibition 6.1 pKd
dovitinib Hs Inhibitor Inhibition 5.9 pKd
AST-487 Hs Inhibitor Inhibition 5.9 pKd
Target used in screen: CDK4-cyclinD3
Ligand Sp. Type Action Value Parameter
R547 Hs Inhibitor Inhibition 9.1 pKd
alvocidib Hs Inhibitor Inhibition 8.5 pKd
AT-7519 Hs Inhibitor Inhibition 7.9 pKd
staurosporine Hs Inhibitor Inhibition 7.7 pKd
lestaurtinib Hs Inhibitor Inhibition 7.5 pKd
BMS-387032 Hs Inhibitor Inhibition 7.2 pKd
ruboxistaurin Hs Inhibitor Inhibition 6.6 pKd
PHA-665752 Hs Inhibitor Inhibition 6.4 pKd
NVP-TAE684 Hs Inhibitor Inhibition 6.4 pKd
AST-487 Hs Inhibitor Inhibition 6.2 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
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

Key to terms and symbols Click column headers to sort
Target used in screen: nd/CDK4/cyclin D1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
K-252a Hs Inhibitor Inhibition 2.9
staurosporine Hs Inhibitor Inhibition 5.0
PKR inhibitor Hs Inhibitor Inhibition 6.2
SB 218078 Hs Inhibitor Inhibition 11.2
alsterpaullone 2-cyanoethyl Hs Inhibitor Inhibition 11.8
JAK3 inhibitor VI Hs Inhibitor Inhibition 14.0
JNJ-7706621 Hs Inhibitor Inhibition 20.0
Gö 6976 Hs Inhibitor Inhibition 27.5
SU9516 Hs Inhibitor Inhibition 33.7
dorsomorphin Hs Inhibitor Inhibition 35.3
Target used in screen: nd/CDK4/cyclin D3
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
K-252a Hs Inhibitor Inhibition 3.4
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 3.7
PKR inhibitor Hs Inhibitor Inhibition 8.3
staurosporine Hs Inhibitor Inhibition 16.0
Cdk4 inhibitor Hs Inhibitor Inhibition 21.1
JAK3 inhibitor VI Hs Inhibitor Inhibition 21.3
SB 218078 Hs Inhibitor Inhibition 22.2
alsterpaullone 2-cyanoethyl Hs Inhibitor Inhibition 25.9
JNJ-7706621 Hs Inhibitor Inhibition 34.7
Gö 6976 Hs Inhibitor Inhibition 44.5
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
Disease:  Dedifferentiated liposarcoma
Synonyms: Liposarcoma [Disease Ontology: DOID:3382]
Disease Ontology: DOID:3382
Orphanet: ORPHA99970
Disease:  Melanoma, cutaneous malignant, susceptibility to, 3; CMM3
Synonyms: Familial melanoma [Orphanet: ORPHA618]
OMIM: 609048
Orphanet: ORPHA618
Disease:  Well-differentiated liposarcoma
Synonyms: Liposarcoma [Disease Ontology: DOID:3382]
Disease Ontology: DOID:3382
Orphanet: ORPHA99971

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. Brain CT, Sung MJ, Lago B. (2015) Pyrrolopyrimidine compounds and their uses. Patent number: US8962630. Assignee: Novartis Ag. Priority date: 22/08/2008. Publication date: 24/02/2015.

5. Brasca MG, Amboldi N, Ballinari D, Cameron A, Casale E, Cervi G, Colombo M, Colotta F, Croci V, D'Alessio R et al.. (2009) Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J. Med. Chem., 52 (16): 5152-63. [PMID:19603809]

6. Carlson BA, Dubay MM, Sausville EA, Brizuela L, Worland PJ. (1996) Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res., 56 (13): 2973-8. [PMID:8674031]

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. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

9. Day PJ, Cleasby A, Tickle IJ, O'Reilly M, Coyle JE, Holding FP, McMenamin RL, Yon J, Chopra R, Lengauer C et al.. (2009) Crystal structure of human CDK4 in complex with a D-type cyclin. Proc. Natl. Acad. Sci. U.S.A., 106 (11): 4166-70. [PMID:19237565]

10. DePinto W, Chu XJ, Yin X, Smith M, Packman K, Goelzer P, Lovey A, Chen Y, Qian H, Hamid R et al.. (2006) In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials. Mol. Cancer Ther., 5 (11): 2644-58. [PMID:17121911]

11. Ding Q, Gillespie P, Kim K, McComas WW, Perrotta A. (2006) Diaminothiazoles having antiproliferative activity. Patent number: US7094896. Assignee: Hoffmann-La Roche Inc.. Priority date: 22/12/2001. Publication date: 22/08/2006.

12. 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]

13. 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]

14. Gray NS, Wodicka L, Thunnissen AM, Norman TC, Kwon S, Espinoza FH, Morgan DO, Barnes G, LeClerc S, Meijer L et al.. (1998) Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science, 281 (5376): 533-8. [PMID:9677190]

15. Hole AJ, Baumli S, Shao H, Shi S, Huang S, Pepper C, Fischer PM, Wang S, Endicott JA, Noble ME. (2013) Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity. J. Med. Chem., 56 (3): 660-70. [PMID:23252711]

16. 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]

17. Jones CD, Andrews DM, Barker AJ, Blades K, Byth KF, Finlay MR, Geh C, Green CP, Johannsen M, Walker M et al.. (2008) Imidazole pyrimidine amides as potent, orally bioavailable cyclin-dependent kinase inhibitors. Bioorg. Med. Chem. Lett., 18 (24): 6486-9. [PMID:18986805]

18. Jorda R, Havlicek L, Sturc A, Tuskova D, Daumova L, Alam M, Skerlova J, Nekardova M, Perina M, Pospíšil T et al.. (2019) 3,5,7-Substituted pyrazolo[4,3-d]pyrimidine inhibitors of cyclindependent kinases and their evaluation in lymphoma models. Journal of Medicinal Chemistry, Just Accepted Manuscript. DOI: 10.1021/acs.jmedchem.9b00189

19. Jorda R, Hendrychová D, Voller J, Řezníčková E, Gucký T, Kryštof V. (2018) How Selective Are Pharmacological Inhibitors of Cell-Cycle-Regulating Cyclin-Dependent Kinases?. J. Med. Chem., 61 (20): 9105-9120. [PMID:30234987]

20. Joshi KS, Rathos MJ, Joshi RD, Sivakumar M, Mascarenhas M, Kamble S, Lal B, Sharma S. (2007) In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. Mol. Cancer Ther., 6 (3): 918-25. [PMID:17363486]

21. Kubo A, Nakagawa K, Varma RK, Conrad NK, Cheng JQ, Lee WC, Testa JR, Johnson BE, Kaye FJ, Kelley MJ. (1999) The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin-dependent kinase 4. Clin. Cancer Res., 5 (12): 4279-86. [PMID:10632371]

22. Lane ME, Yu B, Rice A, Lipson KE, Liang C, Sun L, Tang C, McMahon G, Pestell RG, Wadler S. (2001) A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells. Cancer Res., 61 (16): 6170-7. [PMID:11507069]

23. 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]

24. Pennati M, Campbell AJ, Curto M, Binda M, Cheng Y, Wang LZ, Curtin N, Golding BT, Griffin RJ, Hardcastle IR et al.. (2005) Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation. Mol. Cancer Ther., 4 (9): 1328-37. [PMID:16170024]

25. Ryu CK, Kang HY, Lee SK, Nam KA, Hong CY, Ko WG, Lee BH. (2000) 5-Arylamino-2-methyl-4,7-dioxobenzothiazoles as inhibitors of cyclin-dependent kinase 4 and cytotoxic agents. Bioorg. Med. Chem. Lett., 10 (5): 461-4. [PMID:10743948]

26. Soni R, Muller L, Furet P, Schoepfer J, Stephan C, Zumstein-Mecker S, Fretz H, Chaudhuri B. (2000) Inhibition of cyclin-dependent kinase 4 (Cdk4) by fascaplysin, a marine natural product. Biochem. Biophys. Res. Commun., 275 (3): 877-84. [PMID:10973815]

27. 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]

28. 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.

29. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

30. Zhu G, Conner SE, Zhou X, Shih C, Li T, Anderson BD, Brooks HB, Campbell RM, Considine E, Dempsey JA et al.. (2003) Synthesis, structure-activity relationship, and biological studies of indolocarbazoles as potent cyclin D1-CDK4 inhibitors. J. Med. Chem., 46 (11): 2027-30. [PMID:12747775]

How to cite this page

CDK4 subfamily: cyclin dependent kinase 4. Last modified on 12/11/2019. Accessed on 08/12/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1976.