Target Information

Target General Information

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Target ID

T85799 (Former ID: TTDC00165)

Target Name

Cyclin-dependent kinase 4 (CDK4)

Synonyms

PSK-J3; Cell division protein kinase 4

Gene Name

CDK4

Target Type

Successful target

[1]

Disease

[+] 3 Target-related Diseases

Breast cancer [ICD-11: 2C60-2C6Y]

Lung cancer [ICD-11: 2C25]

Psoriasis [ICD-11: EA90]

Function

Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex. Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition.

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BioChemical Class

Kinase

UniProt ID

CDK4_HUMAN

EC Number

EC 2.7.11.22

Sequence

MATSRYEPVAEIGVGAYGTVYKARDPHSGHFVALKSVRVPNGGGGGGGLPISTVREVALL
RRLEAFEHPNVVRLMDVCATSRTDREIKVTLVFEHVDQDLRTYLDKAPPPGLPAETIKDL
MRQFLRGLDFLHANCIVHRDLKPENILVTSGGTVKLADFGLARIYSYQMALTPVVVTLWY
RAPEVLLQSTYATPVDMWSVGCIFAEMFRRKPLFCGNSEADQLGKIFDLIGLPPEDDWPR
DVSLPRGAFPPRGPRPVQSVVPEMEESGAQLLLEMLTFNPHKRISAFRALQHSYLHKDEG
NPE

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3D Structure

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PDB

HIT2.0 ID

T10S5F

Drugs and Modes of Action

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Approved Drug(s)

[+] 5 Approved Drugs

Apremilast

Drug Info

Approved

Psoriasis vulgaris

[2], [3]

LY2835219

Drug Info

Approved

Breast cancer

[4]

Palbociclib

Drug Info

Approved

Breast cancer

[5]

Ribociclib Succinate

Drug Info

Approved

Hormone receptor positive and HER2-negative advanced or metastatic breast cancer

[6]

Trilaciclib

Drug Info

Approved

Small-cell lung cancer

[7]

Clinical Trial Drug(s)

[+] 14 Clinical Trial Drugs

LEE011

Drug Info

Phase 3

Solid tumour/cancer

[8], [9]

G1T38

Drug Info

Phase 2

Breast cancer

[10]

P-276

Drug Info

Phase 2

Breast cancer

[11], [12]

P276-00

Drug Info

Phase 2

Mantle cell lymphoma

[13]

Ro 31-7453

Drug Info

Phase 2

Solid tumour/cancer

[14]

FCN-437

Drug Info

Phase 1/2

Breast cancer

[15]

GLR2007

Drug Info

Phase 1/2

Non-small-cell lung cancer

[16]

AG-024322

Drug Info

Phase 1

Solid tumour/cancer

[17]

FN-1501

Drug Info

Phase 1

Solid tumour/cancer

[18]

G1T28-1

Drug Info

Phase 1

Solid tumour/cancer

[19]

P1446A-05

Drug Info

Phase 1

Solid tumour/cancer

[20]

PF-07220060

Drug Info

Phase 1

Prostate cancer

[21]

PHA-793887

Drug Info

Phase 1

Solid tumour/cancer

[22]

RGB-286638

Drug Info

Phase 1

Haematological malignancy

[23], [24]

Discontinued Drug(s)

[+] 5 Discontinued Drugs

BAY 10-00394

Drug Info

Discontinued in Phase 2

Small-cell lung cancer

[25], [26]

R547

Drug Info

Discontinued in Phase 1

Advanced solid tumour

[27], [28]

ZK 304709

Drug Info

Discontinued in Phase 1

Advanced solid tumour

[29]

CYC-103

Drug Info

Terminated

Solid tumour/cancer

[31]

PD-0183812

Drug Info

Terminated

Retinoblastoma

[32]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

INOC-005

Drug Info

Preclinical

Solid tumour/cancer

[30]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 55 Inhibitor drugs

Apremilast

Drug Info

[1]

Trilaciclib

Drug Info

[7]

G1T38

Drug Info

[10]

P-276

Drug Info

[20]

P276-00

Drug Info

[17]

Ro 31-7453

Drug Info

[36]

FCN-437

Drug Info

[37]

GLR2007

Drug Info

[38]

AG-024322

Drug Info

[17]

FN-1501

Drug Info

[39]

P1446A-05

Drug Info

[17]

PF-07220060

Drug Info

[21]

PHA-793887

Drug Info

[20]

RGB-286638

Drug Info

[20]

Imidazo pyridine derivative 3

Drug Info

[40]

Indole-based analog 13

Drug Info

[40]

Isoquinoline 1,3-dione derivative 1

Drug Info

[40]

Oxazolyl methylthiothiazole derivative 1

Drug Info

[40]

Palbociclib/ribociclib analog 1

Drug Info

[40]

PMID25726713-Compound-47

Drug Info

[41]

PMID25726713-Compound-48

Drug Info

[41]

PMID25726713-Compound-49

Drug Info

[41]

PMID25726713-Compound-50

Drug Info

[41]

PMID25726713-Compound-51

Drug Info

[41]

PMID25991433-Compound-A1

Drug Info

[42]

PMID26161698-Compound-17

Drug Info

[40]

Pyrrolo[2,3-d]pyrimidine derivative 10

Drug Info

[40]

Pyrrolo[2,3-d]pyrimidine derivative 9

Drug Info

[40]

BAY 10-00394

Drug Info

[20]

R547

Drug Info

[17]

ZK 304709

Drug Info

[17]

INOC-005

Drug Info

[20]

CYC-103

Drug Info

[20]

PD-0183812

Drug Info

[43]

1-(1H-Indazol-6-yl)-3-pyridin-2-yl-urea

Drug Info

[44]

1-(7-Hydroxy-naphthalen-1-yl)-3-pyridin-2-yl-urea

Drug Info

[44]

1-(9-Oxo-9H-fluoren-4-yl)-3-pyridin-2-yl-urea

Drug Info

[44]

1-Pyridin-2-yl-3-quinolin-5-yl-urea

Drug Info

[44]

10-hydroxy-18-methoxybetaenone

Drug Info

[45]

3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione

Drug Info

[46]

3,4-diphenyl-1H-pyrrole-2,5-dione

Drug Info

[46]

3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione

Drug Info

[46]

3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione

Drug Info

[46]

4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol

Drug Info

[47]

Cdk4 inhibitor III

Drug Info

[48]

Fascaplysin

Drug Info

[43]

K00024

Drug Info

[49]

N-(2-(1H-Indol-3-yl)ethyl)biphenyl-4-carboxamide

Drug Info

[50]

NSC-625987

Drug Info

[51]

NU-6102

Drug Info

[52]

NU6140

Drug Info

[53]

PMID18986805C9b

Drug Info

[54]

PYRAZOLOPYRIDAZINE 1

Drug Info

[55]

PYRAZOLOPYRIDAZINE 2

Drug Info

[55]

Ro-0505124

Drug Info

[56]

Modulator

[+] 5 Modulator drugs

LY2835219

Drug Info

[33]

Palbociclib

Drug Info

[5]

Ribociclib Succinate

Drug Info

[34]

LEE011

Drug Info

[35]

G1T28-1

Drug Info

[33]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 17 KEGG Pathways	+
1	Cell cycle
2	p53 signaling pathway
3	PI3K-Akt signaling pathway
4	Tight junction
5	T cell receptor signaling pathway
6	Hepatitis B
7	Measles
8	HTLV-I infection
9	Pathways in cancer
10	Viral carcinogenesis
11	Pancreatic cancer
12	Glioma
13	Melanoma
14	Bladder cancer
15	Chronic myeloid leukemia
16	Small cell lung cancer
17	Non-small cell lung cancer
NetPath Pathway	[+] 3 NetPath Pathways	+
1	TCR Signaling Pathway
2	EGFR1 Signaling Pathway
3	RANKL Signaling Pathway
PID Pathway	[+] 6 PID Pathways	+
1	Regulation of nuclear SMAD2/3 signaling
2	Calcineurin-regulated NFAT-dependent transcription in lymphocytes
3	Validated targets of C-MYC transcriptional activation
4	ATF-2 transcription factor network
5	FOXM1 transcription factor network
6	Regulation of retinoblastoma protein
Reactome	[+] 8 Reactome Pathways	+
1	Oxidative Stress Induced Senescence
2	Senescence-Associated Secretory Phenotype (SASP)
3	Oncogene Induced Senescence
4	RMTs methylate histone arginines
5	Transcriptional regulation of white adipocyte differentiation
6	Ubiquitin-dependent degradation of Cyclin D1
7	Cyclin D associated events in G1
8	Meiotic recombination
WikiPathways	[+] 19 WikiPathways	+
1	DNA Damage Response
2	G1 to S cell cycle control
3	Ovarian Infertility Genes
4	PPAR Alpha Pathway
5	Bladder Cancer
6	S Phase
7	Transcriptional Regulation of White Adipocyte Differentiation
8	Meiotic Recombination
9	Retinoblastoma (RB) in Cancer
10	Spinal Cord Injury
11	Integrated Pancreatic Cancer Pathway
12	Prostate Cancer
13	Signaling Pathways in Glioblastoma
14	TSH signaling pathway
15	Integrated Breast Cancer Pathway
16	Integrated Cancer pathway
17	Mitotic G1-G1/S phases
18	Cell Cycle
19	miRNA Regulation of DNA Damage Response

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 1

Agreement signed with Prostagenics to develop prostate cancer treatment. Innovate Oncology, Inc. 2005.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7372).

REF 3

Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.

REF 4

2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.

REF 5

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2017

REF 6

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2018

REF 7

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021

REF 8

REF 9

ClinicalTrials.gov (NCT01958021) Study of Efficacy and Safety of LEE011 in Postmenopausal Women With Advanced Breast Cancer.(MONALEESA-2). U.S. National Institutes of Health.

REF 10

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 11

REF 12

P276-00, a novel cyclin-dependent inhibitor induces G1-G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models. Mol Cancer Ther. 2007 Mar;6(3):926-34.

REF 13

A phase II, single-arm, open-label, multicenter study to evaluate the efficacy and safety of P276-00, a cyclin-dependent kinase inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2015 Jul;15(7):392-7.

REF 14

A phase 2 study of oral MKC-1, an inhibitor of importin-beta, tubulin, and the mTOR pathway in patients with unresectable or metastatic pancreatic cancer. Invest New Drugs. 2012 Aug;30(4):1614-20.

REF 15

ClinicalTrials.gov (NCT04488107) Safety, Tolerability, Pharmacokinetics and Antitumor Activity of FCN-437c. U.S. National Institutes of Health.

REF 16

ClinicalTrials.gov (NCT04444427) Evaluation of GLR2007 for Advanced Solid Tumors. U.S. National Institutes of Health.

REF 17

Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.

REF 18

ClinicalTrials.gov (NCT03690154) A Phase 1 Study to Evaluate FN-1501 Monotherapy in Patients With Advanced Solid Tumors and R/R AML. U.S. National Institutes of Health.

REF 19

ClinicalTrials.gov (NCT02243150) Safety, Pharmacokinetic and Pharmacodynamic Study of the CDK 4/6 Inhibitor G1T28-1. U.S. National Institutes of Health.

REF 20

Liposarcoma: molecular genetics and therapeutics. Sarcoma. 2011;2011:483154.

REF 21

ClinicalTrials.gov (NCT04557449) Study to Test the Safety and Tolerability of PF-07220060 in Participants With Advance Solid Tumors (CDK4). U.S. National Institutes of Health.

REF 22

A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected h... Cell Cycle. 2011 Mar 15;10(6):963-70.

REF 23

REF 24

ClinicalTrials.gov (NCT01168882) Safety and Tolerability of RGB-286638 in Patients With Selected, Relapsed or Refractory Hematological Malignancies. U.S. National Institutes of Health.

REF 25

REF 26

BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application. Mol Cancer Ther. 2012 Oct;11(10):2265-73.

REF 27

REF 28

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018924)

REF 29

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022386)

REF 30

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022337)

REF 31

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015455)

REF 32

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014130)

REF 33

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

REF 34

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

REF 35

Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82.

REF 36

A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.

REF 37

Clinical pipeline report, company report or official report of Fochon Pharmaceuticals.

REF 38

Clinical pipeline report, company report or official report of Gan & Lee Pharmaceuticals.

REF 39

Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia. J Med Chem. 2018 Feb 22;61(4):1499-1518.

REF 40

Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.

REF 41

Hedgehog inhibitors: a patent review (2013 - present).Expert Opin Ther Pat. 2015 May;25(5):549-65.

REF 42

c-Jun N-terminal kinase inhibitors: a patent review (2010 - 2014).Expert Opin Ther Pat. 2015;25(8):849-72.

REF 43

Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci. 2002 Sep;23(9):417-25.

REF 44

Structure-based generation of a new class of potent Cdk4 inhibitors: new de novo design strategy and library design. J Med Chem. 2001 Dec 20;44(26):4615-27.

REF 45

Anthraquinones and betaenone derivatives from the sponge-associated fungus Microsphaeropsis species: novel inhibitors of protein kinases. J Nat Prod. 2000 Jun;63(6):739-45.

REF 46

Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. J Med Chem. 2006 Feb 23;49(4):1271-81.

REF 47

4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006 Nov 2;49(22):6500-9.

REF 48

5-Arylamino-2-methyl-4,7-dioxobenzothiazoles as inhibitors of cyclin-dependent kinase 4 and cytotoxic agents. Bioorg Med Chem Lett. 2000 Mar 6;10(5):461-4.

REF 49

Synthesis, structure-activity relationship, and biological studies of indolocarbazoles as potent cyclin D1-CDK4 inhibitors. J Med Chem. 2003 May 22;46(11):2027-30.

REF 50

Design, synthesis and biological evaluation of new tryptamine and tetrahydro-beta-carboline-based selective inhibitors of CDK4. Bioorg Med Chem. 2008 Aug 15;16(16):7728-39.

REF 51

The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin-dependent kinase 4. Clin Cancer Res. 1999 Dec;5(12):4279-86.

REF 52

Dissecting the determinants of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 inhibitor selectivity. J Med Chem. 2006 Sep 7;49(18):5470-7.

REF 53

Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation. Mol Cancer Ther. 2005 Sep;4(9):1328-37.

REF 54

Imidazole pyrimidine amides as potent, orally bioavailable cyclin-dependent kinase inhibitors. Bioorg Med Chem Lett. 2008 Dec 15;18(24):6486-9.

REF 55

N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular effi... J Med Chem. 2004 Sep 9;47(19):4716-30.

REF 56

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