Target Information
Target General Infomation | |||||
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Target ID |
T44458
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Former ID |
TTDC00095
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Target Name |
Cell division protein kinase 9
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Gene Name |
CDK9
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Synonyms |
C-2K; CDC2-related kinase; Cyclin-dependent kinase 9; Cyclin-dependent protein kinase Cdk9; Serine/threonine-protein kinase PITALRE; Similar to cyclin-dependent kinase 9; CDK9
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Target Type |
Clinical Trial
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Disease | Advanced solid tumor [ICD9: 140-199; ICD10: C00-C75, C7A, C7B] | ||||
Acute lymphoblastic leukemia [ICD9: 204.0, 556; ICD10: C91.0] | |||||
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] | |||||
Small-cell lung cancer [ICD9: 162.9; ICD10: C33-C34] | |||||
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48] | |||||
Function |
Protein kinase involved in the regulation of transcription. Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR, and the negative elongation factors DSIF and NELF. Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing. TheCDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro. Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single- stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation.
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BioChemical Class |
Kinase
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Target Validation |
T44458
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UniProt ID | |||||
EC Number |
EC 2.7.11.23
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Sequence |
MAKQYDSVECPFCDEVSKYEKLAKIGQGTFGEVFKARHRKTGQKVALKKVLMENEKEGFP
ITALREIKILQLLKHENVVNLIEICRTKASPYNRCKGSIYLVFDFCEHDLAGLLSNVLVK FTLSEIKRVMQMLLNGLYYIHRNKILHRDMKAANVLITRDGVLKLADFGLARAFSLAKNS QPNRYTNRVVTLWYRPPELLLGERDYGPPIDLWGAGCIMAEMWTRSPIMQGNTEQHQLAL ISQLCGSITPEVWPNVDNYELYEKLELVKGQKRKVKDRLKAYVRDPYALDLIDKLLVLDP AQRIDSDDALNHDFFWSDPMPSDLKGMLSTHLTSMFEYLAPPRRKGSQITQQSTNQSRNP ATTNQTEFERVF |
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Drugs and Mode of Action | |||||
Drug(s) | P276-00 | Drug Info | Phase 2 | Mantle cell lymphoma | [533193] |
RGB-286638 | Drug Info | Phase 1 | Hematological malignancies | [523121], [542709] | |
SNS-032 | Drug Info | Phase 1 | Solid tumours | [537097], [541014] | |
SCH 727965 | Drug Info | Discontinued in Phase 3 | Acute lymphoblastic leukemia | [531565], [533028], [542400] | |
BAY 10-00394 | Drug Info | Discontinued in Phase 2 | Small-cell lung cancer | [531973], [542800] | |
ZK 304709 | Drug Info | Discontinued in Phase 1 | Advanced solid tumor | [548143] | |
Inhibitor | 3-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol | Drug Info | [528490] | ||
4-(phenyldiazenyl)-1H-pyrazole-3,5-diamine | Drug Info | [528490] | |||
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol | Drug Info | [528490] | |||
BAY 10-00394 | Drug Info | [550520] | |||
compound 18 | Drug Info | [531180] | |||
compound 89S | Drug Info | [529892] | |||
MERIOLIN 1 | Drug Info | [529275] | |||
MERIOLIN 2 | Drug Info | [529275] | |||
MERIOLIN 3 | Drug Info | [529275] | |||
MERIOLIN 4 | Drug Info | [529275] | |||
MERIOLIN 5 | Drug Info | [529275] | |||
MERIOLIN 6 | Drug Info | [529275] | |||
MERIOLIN 7 | Drug Info | [529275] | |||
MERIOLIN 8 | Drug Info | [529275] | |||
NVP-2 | Drug Info | [543530] | |||
P276-00 | Drug Info | [537564] | |||
RGB-286638 | Drug Info | [532412] | |||
SCH 727965 | Drug Info | [537564] | |||
SNS-032 | Drug Info | [537097], [537228] | |||
ZK 304709 | Drug Info | [537564] | |||
Binder | Deschloroflavopiridol | Drug Info | [535564] | ||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
KEGG Pathway | Transcriptional misregulation in cancer | ||||
NetPath Pathway | EGFR1 Signaling Pathway | ||||
Reactome | SMAD4 heterotrimer regulates transcription | ||||
WikiPathways | Cardiac Hypertrophic Response | ||||
SMAD4 heterotrimer | |||||
Host Interactions of HIV factors | |||||
HIV Life Cycle | |||||
IL-9 Signaling Pathway | |||||
RNA Polymerase II Transcription | |||||
MicroRNAs in cardiomyocyte hypertrophy | |||||
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 531565 | Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models. Cancer Biol Ther. 2011 Oct 1;12(7):598-609. Epub 2011 Oct 1. | ||||
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 533028 | Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015 Jan 15;125(3):443-8. | ||||
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 537097 | Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2009 May 7;113(19):4637-45. Epub 2009 Feb 20. | ||||
Ref 541014 | (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: 5670). | ||||
Ref 542400 | (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: 7379). | ||||
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 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 529275 | J Med Chem. 2008 Feb 28;51(4):737-51. Epub 2008 Jan 31.Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolincomplex. | ||||
Ref 529892 | First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. J Med Chem. 2009 Jan 22;52(2):293-307. | ||||
Ref 531180 | Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding. J Med Chem. 2010 Oct 28;53(20):7296-315. | ||||
Ref 532412 | Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia. 2013 Dec;27(12):2366-75. | ||||
Ref 535564 | Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci. 2002 Sep;23(9):417-25. | ||||
Ref 537097 | Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2009 May 7;113(19):4637-45. Epub 2009 Feb 20. | ||||
Ref 537228 | Development of cell-cycle inhibitors for cancer therapy. Curr Oncol. 2009 Mar;16(2):36-43. | ||||
Ref 537564 | Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. |
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