Target Information

Target General Information

Target ID

T44458 (Former ID: TTDC00095)

Target Name

Cyclin-dependent kinase 9 (CDK9)

Synonyms

Tat-associated kinase complex catalytic subunit; TAK; Similar to cyclin-dependent kinase 9; Serine/threonine-protein kinase PITALRE; Cyclin-dependent protein kinase Cdk9; Cell division protein kinase 9; Cell division cycle 2-like protein kinase 4; CDC2L4; CDC2-related kinase; C-2K

Gene Name

CDK9

Target Type

Clinical trial target

[1]

Disease

[+] 5 Target-related Diseases

Acute myeloid leukaemia [ICD-11: 2A60]

Mature B-cell lymphoma [ICD-11: 2A85]

Lymphoma [ICD-11: 2A80-2A86]

Malignant haematopoietic neoplasm [ICD-11: 2B33]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Function

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. The CDK9/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. Protein kinase involved in the regulation of transcription.

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BioChemical Class

Kinase

UniProt ID

CDK9_HUMAN

EC Number

EC 2.7.11.22

Sequence

MAKQYDSVECPFCDEVSKYEKLAKIGQGTFGEVFKARHRKTGQKVALKKVLMENEKEGFP
ITALREIKILQLLKHENVVNLIEICRTKASPYNRCKGSIYLVFDFCEHDLAGLLSNVLVK
FTLSEIKRVMQMLLNGLYYIHRNKILHRDMKAANVLITRDGVLKLADFGLARAFSLAKNS
QPNRYTNRVVTLWYRPPELLLGERDYGPPIDLWGAGCIMAEMWTRSPIMQGNTEQHQLAL
ISQLCGSITPEVWPNVDNYELYEKLELVKGQKRKVKDRLKAYVRDPYALDLIDKLLVLDP
AQRIDSDDALNHDFFWSDPMPSDLKGMLSTHLTSMFEYLAPPRRKGSQITQQSTNQSRNP
ATTNQTEFERVF

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3D Structure

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PDB

HIT2.0 ID

T32R5L

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 8 Clinical Trial Drugs

Flavopiridol

Drug Info

Phase 2

Acute myeloid leukaemia

[2], [3]

P276-00

Drug Info

Phase 2

Mantle cell lymphoma

[4]

AZD4573

Drug Info

Phase 1

Haematological malignancy

[3]

BTX-A51

Drug Info

Phase 1

Non-hodgkin lymphoma

[5]

CYC065

Drug Info

Phase 1

Lymphoma

[3]

RGB-286638

Drug Info

Phase 1

Haematological malignancy

[6], [7]

SNS-032

Drug Info

Phase 1

Solid tumour/cancer

[8], [9]

TP-1287

Drug Info

Phase 1

Solid tumour/cancer

[10]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

SCH 727965

Drug Info

Discontinued in Phase 3

Acute lymphoblastic leukaemia

[11], [12], [13]

BAY 10-00394

Drug Info

Discontinued in Phase 2

Small-cell lung cancer

[14], [15]

ZK 304709

Drug Info

Discontinued in Phase 1

Advanced solid tumour

[16]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

NVP-2

Drug Info

Preclinical

Solid tumour/cancer

[17]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 51 Inhibitor drugs

Flavopiridol

Drug Info

[3]

P276-00

Drug Info

[1]

AZD4573

Drug Info

[3]

BTX-A51

Drug Info

[18]

CYC065

Drug Info

[3]

RGB-286638

Drug Info

[19]

SNS-032

Drug Info

[9], [20]

TP-1287

Drug Info

[21]

1,5-di-substituted pyridine derivative 1

Drug Info

[22]

4-(thiazol-5-yl)-pyrimidine derivative 1

Drug Info

[22]

4-(thiazol-5-yl)-pyrimidine derivative 2

Drug Info

[22]

5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivative 1

Drug Info

[22]

Alkyl sulfone derivative 1

Drug Info

[22]

Aminoarylpyridine derivative 1

Drug Info

[22]

Aryl pyrimidine derivative 1

Drug Info

[22]

Benzothiazine derivative 1

Drug Info

[22]

Bipyridine derivative 1

Drug Info

[22]

Diaryl amine derivative 1

Drug Info

[22]

Flavopiridol analog 1

Drug Info

[22]

Indole-based analog 13

Drug Info

[22]

N-(pyridin-2-yl)pyridine methylsulfone derivative 1

Drug Info

[22]

N-(pyridin-2-yl)pyrimidin-4-amine derivative 1

Drug Info

[22]

N-(pyridin-2-yl)pyrimidin-4-amine derivative 2

Drug Info

[22]

N-phenyl-pyrimidin-4-amine derivative 1

Drug Info

[22]

Nitrogen mustard derivative 1

Drug Info

[22]

Oxazolyl methylthiothiazole derivative 1

Drug Info

[22]

Phenylpyridine derivative 1

Drug Info

[22]

Phenylpyridine derivative 2

Drug Info

[22]

PMID26161698-Compound-25

Drug Info

[22]

PMID26161698-Compound-32

Drug Info

[22]

Pyrazinylpyridine derivative 1

Drug Info

[22]

Pyrazolo[1,5-a]-1,3,5-triazine derivative 1

Drug Info

[22]

Roscovitine derivative 1

Drug Info

[22]

Tricyclic benzimidazole derivative 1

Drug Info

[22]

SCH 727965

Drug Info

[1]

BAY 10-00394

Drug Info

[23]

ZK 304709

Drug Info

[1]

NVP-2

Drug Info

[24]

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

Drug Info

[25]

4-(phenyldiazenyl)-1H-pyrazole-3,5-diamine

Drug Info

[25]

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

Drug Info

[25]

MERIOLIN 1

Drug Info

[27]

MERIOLIN 2

Drug Info

[27]

MERIOLIN 3

Drug Info

[27]

MERIOLIN 4

Drug Info

[27]

MERIOLIN 5

Drug Info

[27]

MERIOLIN 6

Drug Info

[27]

MERIOLIN 7

Drug Info

[27]

MERIOLIN 8

Drug Info

[27]

PMID19115845C89S

Drug Info

[28]

PMID20873740C18

Drug Info

[29]

Binder

[+] 1 Binder drugs

Deschloroflavopiridol

Drug Info

[26]

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 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

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KEGG Pathway

[+] 1 KEGG Pathways

Transcriptional misregulation in cancer

NetPath Pathway

[+] 1 NetPath Pathways

EGFR1 Signaling Pathway

Reactome

[+] 1 Reactome Pathways

SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription

WikiPathways

[+] 7 WikiPathways

Cardiac Hypertrophic Response

Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer

Host Interactions of HIV factors

HIV Life Cycle

IL-9 Signaling Pathway

RNA Polymerase II Transcription

MicroRNAs in cardiomyocyte hypertrophy

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 1

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

REF 2

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

REF 3

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

REF 4

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 5

ClinicalTrials.gov (NCT04872166) A Study of BTX-A51 in People With Advanced Solid Tumor or Non-Hodgkin Lymphoma. U.S. National Institutes of Health.

REF 6

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: 7744).

REF 7

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 8

REF 9

Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2009 May 7;113(19):4637-45.

REF 10

ClinicalTrials.gov (NCT03604783) Phase 1, First-in-human Study of Oral TP-1287 in Patients With Advanced Solid Tumors. U.S. National Institutes of Health.

REF 11

REF 12

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 13

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.

REF 14

REF 15

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 16

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 17

Kinase inhibitors: the road ahead. Nat Rev Drug Discov. 2018 May;17(5):353-377.

REF 18

Clinical pipeline report, company report or official report of BioTheryX.

REF 19

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 20

Development of cell-cycle inhibitors for cancer therapy. Curr Oncol. 2009 Mar;16(2):36-43.

REF 21

Clinical pipeline report, company report or official report of Sumitomo Dainippon Pharma.

REF 22

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

REF 23

National Cancer Institute Drug Dictionary (drug id 770319).

REF 24

REF 25

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 26

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

REF 27

Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolin com... J Med Chem. 2008 Feb 28;51(4):737-51.

REF 28

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 29

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.

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