Target General Infomation
Target ID
T85799
Former ID
TTDC00165
Target Name
Cell division protein kinase 4
Gene Name
CDK4
Synonyms
Cyclin-dependent kinase 4; PSK-J3; CDK4
Target Type
Successful
Disease Advanced solid tumor [ICD9: 140-199; ICD10: C00-C75, C7A, C7B]
Breast cancer [ICD9: 174, 175; ICD10: C50]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Hormone receptor-positive and HER2-negative advanced or metastatic breast cancer [ICD10: C50]
Hematological malignancies [ICD9: 200-209; ICD10: C81-C86]
Mantle cell lymphoma [ICD9: 200.4, 202.8, 203.0, 208.9; ICD10: C81-C86, C85.7, C90.0, C91-C95]
Psoriasis [ICD9: 696; ICD10: L40]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Small-cell lung cancer [ICD9: 162.9; ICD10: C33-C34]
Function
Ser/Thr-kinasecomponent 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. 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.
BioChemical Class
Kinase
Target Validation
T85799
UniProt ID
EC Number
EC 2.7.11.22
Sequence
MATSRYEPVAEIGVGAYGTVYKARDPHSGHFVALKSVRVPNGGGGGGGLPISTVREVALL
RRLEAFEHPNVVRLMDVCATSRTDREIKVTLVFEHVDQDLRTYLDKAPPPGLPAETIKDL
MRQFLRGLDFLHANCIVHRDLKPENILVTSGGTVKLADFGLARIYSYQMALTPVVVTLWY
RAPEVLLQSTYATPVDMWSVGCIFAEMFRRKPLFCGNSEADQLGKIFDLIGLPPEDDWPR
DVSLPRGAFPPRGPRPVQSVVPEMEESGAQLLLEMLTFNPHKRISAFRALQHSYLHKDEG
NPE
Structure
1LD2; 2W96; 2W99; 2W9F; 2W9Z; 3G33
Drugs and Mode of Action
Drug(s) Ribociclib Succinate Drug Info Approved Hormone receptor-positive and HER2-negative advanced or metastatic breast cancer [889446]
LEE011 Drug Info Phase 3 Cancer [524461], [542405]
LY2835219 Drug Info Phase 3 Cancer [524783], [542404]
P-276 Drug Info Phase 2 Breast cancer [528734], [542849]
P276-00 Drug Info Phase 2 Mantle cell lymphoma [533193]
PD-332991 Drug Info Phase 2 Cancer [524116]
Ro 31-7453 Drug Info Phase 2 Solid tumours [531583]
AG-024322 Drug Info Phase 1 Cancer [537564]
G1T28-1 Drug Info Phase 1 Cancer [524917]
P1446A-05 Drug Info Phase 1 Cancer [531342]
PHA-793887 Drug Info Phase 1 Cancer [531377]
RGB-286638 Drug Info Phase 1 Hematological malignancies [523121], [542709]
INOC-005 Drug Info Preclinical Cancer [548139]
Capridine-beta Drug Info Discontinued in Phase 4 Psoriasis [533123]
BAY 10-00394 Drug Info Discontinued in Phase 2 Small-cell lung cancer [531973], [542800]
R547 Drug Info Discontinued in Phase 1 Advanced solid tumor [541047], [547737]
ZK 304709 Drug Info Discontinued in Phase 1 Advanced solid tumor [548143]
CYC-103 Drug Info Terminated Cancer [547357]
Inhibitor 1-(1H-Indazol-6-yl)-3-pyridin-2-yl-urea Drug Info [526223]
1-(7-Hydroxy-naphthalen-1-yl)-3-pyridin-2-yl-urea Drug Info [526223]
1-(9-Oxo-9H-fluoren-4-yl)-3-pyridin-2-yl-urea Drug Info [526223]
1-Pyridin-2-yl-3-quinolin-5-yl-urea Drug Info [526223]
10-hydroxy-18-methoxybetaenone Drug Info [525806]
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione Drug Info [528032]
3,4-diphenyl-1H-pyrrole-2,5-dione Drug Info [528032]
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione Drug Info [528032]
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione Drug Info [528032]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol Drug Info [528490]
AG-024322 Drug Info [537564]
BAY 10-00394 Drug Info [531342]
Capridine-beta Drug Info [551434]
Cdk4 inhibitor III Drug Info [525734]
compound 9b Drug Info [529792]
CYC-103 Drug Info [531342]
Fascaplysin Drug Info [535564]
INOC-005 Drug Info [531342]
K00024 Drug Info [526625]
N-(2-(1H-Indol-3-yl)ethyl)biphenyl-4-carboxamide Drug Info [529613]
NSC-625987 Drug Info [525671]
NU-6102 Drug Info [528404]
NU6140 Drug Info [527749]
P-276 Drug Info [531342]
P1446A-05 Drug Info [537564]
P276-00 Drug Info [537564]
PD0183813 Drug Info [535564]
PHA-793887 Drug Info [531342]
PYRAZOLOPYRIDAZINE 1 Drug Info [527192]
PYRAZOLOPYRIDAZINE 2 Drug Info [527192]
R547 Drug Info [537564]
RGB-286638 Drug Info [531342]
Ro 31-7453 Drug Info [536474]
Ro-0505124 Drug Info [543529]
ZK 304709 Drug Info [537564]
Modulator G1T28-1 Drug Info [1572591]
LEE011 Drug Info [532480]
LY2835219 Drug Info [1572591]
PD-332991 Drug Info
Ribociclib Succinate Drug Info [556264]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Cell cycle
p53 signaling pathway
PI3K-Akt signaling pathway
Tight junction
T cell receptor signaling pathway
Hepatitis B
Measles
HTLV-I infection
Pathways in cancer
Viral carcinogenesis
Pancreatic cancer
Glioma
Melanoma
Bladder cancer
Chronic myeloid leukemia
Small cell lung cancer
Non-small cell lung cancer
NetPath Pathway TCR Signaling Pathway
EGFR1 Signaling Pathway
RANKL Signaling Pathway
Pathway Interaction Database Regulation of nuclear SMAD2/3 signaling
Calcineurin-regulated NFAT-dependent transcription in lymphocytes
Validated targets of C-MYC transcriptional activation
ATF-2 transcription factor network
FOXM1 transcription factor network
Regulation of retinoblastoma protein
Reactome Oxidative Stress Induced Senescence
Senescence-Associated Secretory Phenotype (SASP)
Oncogene Induced Senescence
RMTs methylate histone arginines
Transcriptional regulation of white adipocyte differentiation
Ubiquitin-dependent degradation of Cyclin D1
Cyclin D associated events in G1
Meiotic recombination
WikiPathways DNA Damage Response
G1 to S cell cycle control
Ovarian Infertility Genes
PPAR Alpha Pathway
Bladder Cancer
S Phase
Transcriptional Regulation of White Adipocyte Differentiation
Meiotic Recombination
Retinoblastoma (RB) in Cancer
Spinal Cord Injury
Integrated Pancreatic Cancer Pathway
Prostate Cancer
Signaling Pathways in Glioblastoma
TSH signaling pathway
Integrated Breast Cancer Pathway
Integrated Cancer pathway
Mitotic G1-G1/S phases
Cell Cycle
miRNA Regulation of DNA Damage Response
References
Ref 523121ClinicalTrials.gov (NCT01168882) Safety and Tolerability of RGB-286638 in Patients With Selected, Relapsed or Refractory Hematological Malignancies. U.S. National Institutes of Health.
Ref 524116ClinicalTrials.gov (NCT01723774) PD 0332991 and Anastrozole for Stage 2 or 3 Estrogen Receptor Positive and HER2 Negative Breast Cancer. U.S. National Institutes of Health.
Ref 524461ClinicalTrials.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 524783ClinicalTrials.gov (NCT02152631) A Study of Abemaciclib (LY2835219) in Participants With Previously Treated Lung Cancer. U.S. National Institutes of Health.
Ref 524917ClinicalTrials.gov (NCT02243150) Safety, Pharmacokinetic and Pharmacodynamic Study of the CDK 4/6 Inhibitor G1T28-1. U.S. National Institutes of Health.
Ref 528734P276-00, 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 531342Liposarcoma: molecular genetics and therapeutics. Sarcoma. 2011;2011:483154.
Ref 531377A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors. Cell Cycle. 2011 Mar 15;10(6):963-70. Epub 2011 Mar 15.
Ref 531583A 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 531973BAY 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 5331232014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
Ref 533193A 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 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 541047(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: 5707).
Ref 542404(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: 7382).
Ref 542405(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: 7383).
Ref 542709(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: 7744).
Ref 542800(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: 7874).
Ref 542849(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: 7934).
Ref 547357Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015455)
Ref 547737Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018924)
Ref 548139Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022337)
Ref 548143Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022386)
Ref 889446Drugs@FDA (Edaravone)
Ref
Ref 525671The 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 5257345-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 525806J Nat Prod. 2000 Jun;63(6):739-45.Anthraquinones and betaenone derivatives from the sponge-associated fungus Microsphaeropsis species: novel inhibitors of protein kinases.
Ref 526223J Med Chem. 2001 Dec 20;44(26):4615-27.Structure-based generation of a new class of potent Cdk4 inhibitors: new de novo design strategy and library design.
Ref 526625Synthesis, 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 527192J Med Chem. 2004 Sep 9;47(19):4716-30.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 efficacy.
Ref 527749Potentiation 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 528032J Med Chem. 2006 Feb 23;49(4):1271-81.Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors.
Ref 528404J Med Chem. 2006 Sep 7;49(18):5470-7.Dissecting the determinants of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 inhibitor selectivity.
Ref 528490J Med Chem. 2006 Nov 2;49(22):6500-9.4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
Ref 529613Bioorg Med Chem. 2008 Aug 15;16(16):7728-39. Epub 2008 Jul 8.Design, synthesis and biological evaluation of new tryptamine and tetrahydro-beta-carboline-based selective inhibitors of CDK4.
Ref 529792Bioorg Med Chem Lett. 2008 Dec 15;18(24):6486-9. Epub 2008 Oct 22.Imidazole pyrimidine amides as potent, orally bioavailable cyclin-dependent kinase inhibitors.
Ref 531342Liposarcoma: molecular genetics and therapeutics. Sarcoma. 2011;2011:483154.
Ref 532480Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82.
Ref 535564Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci. 2002 Sep;23(9):417-25.
Ref 536474A 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 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 543529(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. (Target id: 1976).
Ref 551434Agreement signed with Prostagenics to develop prostate cancer treatment. Innovate Oncology, Inc. 2005.
Ref 556264Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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