Target Information
Target General Information | Top | |||||
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Target ID |
T89361
(Former ID: TTDC00169)
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Target Name |
Cyclin-dependent kinase 6 (CDK6)
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Synonyms |
Serine/threonine-protein kinase PLSTIRE; Serine/threonine protein kinase PLSTIRE; Cell division protein kinase 6; CDKN6
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Gene Name |
CDK6
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Breast cancer [ICD-11: 2C60-2C6Y] | |||||
2 | Lung cancer [ICD-11: 2C25] | |||||
3 | Psoriasis [ICD-11: EA90] | |||||
Function |
Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e. g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans. May play a role in the centrosome organization during the cell cycle phases. Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition.
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BioChemical Class |
Kinase
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UniProt ID | ||||||
EC Number |
EC 2.7.11.22
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Sequence |
MEKDGLCRADQQYECVAEIGEGAYGKVFKARDLKNGGRFVALKRVRVQTGEEGMPLSTIR
EVAVLRHLETFEHPNVVRLFDVCTVSRTDRETKLTLVFEHVDQDLTTYLDKVPEPGVPTE TIKDMMFQLLRGLDFLHSHRVVHRDLKPQNILVTSSGQIKLADFGLARIYSFQMALTSVV VTLWYRAPEVLLQSSYATPVDLWSVGCIFAEMFRRKPLFRGSSDVDQLGKILDVIGLPGE EDWPRDVALPRQAFHSKSAQPIEKFVTDIDELGKDLLLKCLTFNPAKRISAYSALSHPYF QDLERCKENLDSHLPPSQNTSELNTA Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T22IMH |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 5 Approved Drugs | + | ||||
1 | Apremilast | Drug Info | Approved | Psoriasis vulgaris | [2], [3] | |
2 | LY2835219 | Drug Info | Approved | Breast cancer | [4] | |
3 | Palbociclib | Drug Info | Approved | Breast cancer | [5] | |
4 | Ribociclib Succinate | Drug Info | Approved | Hormone receptor positive and HER2-negative advanced or metastatic breast cancer | [6] | |
5 | Trilaciclib | Drug Info | Approved | Small-cell lung cancer | [7] | |
Clinical Trial Drug(s) | [+] 6 Clinical Trial Drugs | + | ||||
1 | LEE011 | Drug Info | Phase 3 | Solid tumour/cancer | [8], [9] | |
2 | G1T38 | Drug Info | Phase 2 | Breast cancer | [10] | |
3 | FCN-437 | Drug Info | Phase 1/2 | Breast cancer | [11] | |
4 | GLR2007 | Drug Info | Phase 1/2 | Non-small-cell lung cancer | [12] | |
5 | FN-1501 | Drug Info | Phase 1 | Solid tumour/cancer | [13] | |
6 | G1T28-1 | Drug Info | Phase 1 | Solid tumour/cancer | [14] | |
Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
1 | INOC-005 | Drug Info | Preclinical | Solid tumour/cancer | [15] | |
Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
1 | CYC-103 | Drug Info | Terminated | Solid tumour/cancer | [16] | |
2 | PD-0183812 | Drug Info | Terminated | Retinoblastoma | [17] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 25 Inhibitor drugs | + | ||||
1 | Apremilast | Drug Info | [1] | |||
2 | Trilaciclib | Drug Info | [7] | |||
3 | G1T38 | Drug Info | [10] | |||
4 | FCN-437 | Drug Info | [21] | |||
5 | GLR2007 | Drug Info | [22] | |||
6 | FN-1501 | Drug Info | [23] | |||
7 | Isoquinoline 1,3-dione derivative 1 | Drug Info | [24] | |||
8 | Oxazolyl methylthiothiazole derivative 1 | Drug Info | [24] | |||
9 | PMID25726713-Compound-47 | Drug Info | [25] | |||
10 | PMID25726713-Compound-48 | Drug Info | [25] | |||
11 | PMID25726713-Compound-49 | Drug Info | [25] | |||
12 | PMID25726713-Compound-50 | Drug Info | [25] | |||
13 | PMID25726713-Compound-51 | Drug Info | [25] | |||
14 | INOC-005 | Drug Info | [26] | |||
15 | CYC-103 | Drug Info | [27] | |||
16 | PD-0183812 | Drug Info | [28] | |||
17 | 3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione | Drug Info | [29] | |||
18 | 3,4-diphenyl-1H-pyrrole-2,5-dione | Drug Info | [29] | |||
19 | 3,7,3',4'-TETRAHYDROXYFLAVONE | Drug Info | [30], [31] | |||
20 | 3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione | Drug Info | [29] | |||
21 | APIGENIN | Drug Info | [31] | |||
22 | Chrysin | Drug Info | [31] | |||
23 | Deschloroflavopiridol | Drug Info | [28] | |||
24 | Fascaplysin | Drug Info | [28] | |||
25 | RGB-286147 | Drug Info | [32] | |||
Modulator | [+] 5 Modulator drugs | + | ||||
1 | LY2835219 | Drug Info | [18] | |||
2 | Palbociclib | Drug Info | [5] | |||
3 | Ribociclib Succinate | Drug Info | [19] | |||
4 | LEE011 | Drug Info | [20] | |||
5 | G1T28-1 | Drug Info | [18] |
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"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 | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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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 | 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: 7383). | |||||
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 | ClinicalTrials.gov (NCT04488107) Safety, Tolerability, Pharmacokinetics and Antitumor Activity of FCN-437c. U.S. National Institutes of Health. | |||||
REF 12 | ClinicalTrials.gov (NCT04444427) Evaluation of GLR2007 for Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
REF 13 | 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 14 | ClinicalTrials.gov (NCT02243150) Safety, Pharmacokinetic and Pharmacodynamic Study of the CDK 4/6 Inhibitor G1T28-1. U.S. National Institutes of Health. | |||||
REF 15 | 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 16 | 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 17 | 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 18 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
REF 19 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. | |||||
REF 20 | Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82. | |||||
REF 21 | Clinical pipeline report, company report or official report of Fochon Pharmaceuticals. | |||||
REF 22 | Clinical pipeline report, company report or official report of Gan & Lee Pharmaceuticals. | |||||
REF 23 | 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 24 | Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70. | |||||
REF 25 | Hedgehog inhibitors: a patent review (2013 - present).Expert Opin Ther Pat. 2015 May;25(5):549-65. | |||||
REF 26 | What are next generation innovative therapeutic targets. J Pharmacol Exp Ther. 2009 Jul;330(1):304-15. | |||||
REF 27 | WO patent application no. 2007,0898,78, Sutures and anti-scarring agents. | |||||
REF 28 | Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci. 2002 Sep;23(9):417-25. | |||||
REF 29 | Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. J Med Chem. 2006 Feb 23;49(4):1271-81. | |||||
REF 30 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
REF 31 | Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin. J Med Chem. 2005 Feb 10;48(3):737-43. | |||||
REF 32 | A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8. |
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