Target Information
Target General Infomation | |||||
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Target ID |
T85799
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Former ID |
TTDC00165
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Target Name |
Cell division protein kinase 4
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Gene Name |
CDK4
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Synonyms |
Cyclin-dependent kinase 4; PSK-J3; CDK4
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Target Type |
Successful
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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.
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BioChemical Class |
Kinase
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Target Validation |
T85799
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UniProt ID | |||||
EC Number |
EC 2.7.11.22
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Sequence |
MATSRYEPVAEIGVGAYGTVYKARDPHSGHFVALKSVRVPNGGGGGGGLPISTVREVALL
RRLEAFEHPNVVRLMDVCATSRTDREIKVTLVFEHVDQDLRTYLDKAPPPGLPAETIKDL MRQFLRGLDFLHANCIVHRDLKPENILVTSGGTVKLADFGLARIYSYQMALTPVVVTLWY RAPEVLLQSTYATPVDMWSVGCIFAEMFRRKPLFCGNSEADQLGKIFDLIGLPPEDDWPR DVSLPRGAFPPRGPRPVQSVVPEMEESGAQLLLEMLTFNPHKRISAFRALQHSYLHKDEG NPE |
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Structure |
1LD2; 2W96; 2W99; 2W9F; 2W9Z; 3G33
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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 523121 | 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 524116 | ClinicalTrials.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 524461 | 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 524783 | ClinicalTrials.gov (NCT02152631) A Study of Abemaciclib (LY2835219) in Participants With Previously Treated Lung Cancer. U.S. National Institutes of Health. | ||||
Ref 524917 | ClinicalTrials.gov (NCT02243150) Safety, Pharmacokinetic and Pharmacodynamic Study of the CDK 4/6 Inhibitor G1T28-1. U.S. National Institutes of Health. | ||||
Ref 528734 | 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 531377 | 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 hepatotoxicity in patients with solid tumors. Cell Cycle. 2011 Mar 15;10(6):963-70. Epub 2011 Mar 15. | ||||
Ref 531583 | 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 531973 | 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 533193 | 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 537564 | Cell 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 547357 | 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 547737 | 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 548139 | 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 525671 | 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 525734 | 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 525806 | J 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 526223 | J 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 526625 | 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 527192 | J 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 527749 | 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 528032 | J Med Chem. 2006 Feb 23;49(4):1271-81.Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. | ||||
Ref 528404 | J 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 528490 | J 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 529613 | Bioorg 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 529792 | Bioorg 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 532480 | Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82. | ||||
Ref 535564 | Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci. 2002 Sep;23(9):417-25. | ||||
Ref 536474 | 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 537564 | Cell 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 551434 | Agreement signed with Prostagenics to develop prostate cancer treatment. Innovate Oncology, Inc. 2005. |
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