Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT1LVF2)

• DTT 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
• DTT Type: Clinical trial target; [1]
• Related Disease:
  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]
• BioChemical Class: Kinase
• UniProt ID: CDK9_HUMAN
• TTD ID: T44458
• EC Number: EC 2.7.11.22
• Sequence:
  MAKQYDSVECPFCDEVSKYEKLAKIGQGTFGEVFKARHRKTGQKVALKKVLMENEKEGFP
  ITALREIKILQLLKHENVVNLIEICRTKASPYNRCKGSIYLVFDFCEHDLAGLLSNVLVK
  FTLSEIKRVMQMLLNGLYYIHRNKILHRDMKAANVLITRDGVLKLADFGLARAFSLAKNS
  QPNRYTNRVVTLWYRPPELLLGERDYGPPIDLWGAGCIMAEMWTRSPIMQGNTEQHQLAL
  ISQLCGSITPEVWPNVDNYELYEKLELVKGQKRKVKDRLKAYVRDPYALDLIDKLLVLDP
  AQRIDSDDALNHDFFWSDPMPSDLKGMLSTHLTSMFEYLAPPRRKGSQITQQSTNQSRNP
  ATTNQTEFERVF
• 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.
• Reactome Pathway: SMAD2/SMAD3 (R-HSA-2173796)

Molecular Interaction Atlas (MIA) of This DTT

8 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Flavopiridol	DMKSUOI	Acute myeloid leukaemia	2A60	Phase 2	[2]
P276-00	DM9DJL2	Mantle cell lymphoma	2A85.5	Phase 2	[1]
AZD4573	DMOYPTK	Haematological malignancy	2B33.Y	Phase 1	[2]
BTX-A51	DMC8XHQ	Advanced solid tumour	2A00-2F9Z	Phase 1	[3]
CYC065	DM9ODT6	Lymphoma	2A80-2A86	Phase 1	[2]
RGB-286638	DMEGOQP	Haematological malignancy	2B33.Y	Phase 1	[4]
SNS-032	DMEITAS	Solid tumour/cancer	2A00-2F9Z	Phase 1	[5], [6]
TP-1287	DM3Z07E	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]

26 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1,5-di-substituted pyridine derivative 1	DMEUO8G	N. A.	N. A.	Patented	[8]
4-(thiazol-5-yl)-pyrimidine derivative 1	DM7B81V	N. A.	N. A.	Patented	[8]
4-(thiazol-5-yl)-pyrimidine derivative 2	DMMQFCN	N. A.	N. A.	Patented	[8]
5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivative 1	DMHXKFB	N. A.	N. A.	Patented	[8]
Alkyl sulfone derivative 1	DM06U3J	N. A.	N. A.	Patented	[8]
Aminoarylpyridine derivative 1	DMQVZY5	N. A.	N. A.	Patented	[8]
Aryl pyrimidine derivative 1	DM3CVWU	N. A.	N. A.	Patented	[8]
Benzothiazine derivative 1	DMMVHY4	N. A.	N. A.	Patented	[8]
Bipyridine derivative 1	DMPUXL3	N. A.	N. A.	Patented	[8]
Diaryl amine derivative 1	DM06MJH	N. A.	N. A.	Patented	[8]
Flavopiridol analog 1	DMXL3A5	N. A.	N. A.	Patented	[8]
Indole-based analog 13	DMV7DFM	N. A.	N. A.	Patented	[8]
N-(pyridin-2-yl)pyridine methylsulfone derivative 1	DM305UL	N. A.	N. A.	Patented	[8]
N-(pyridin-2-yl)pyrimidin-4-amine derivative 1	DMRE2I3	N. A.	N. A.	Patented	[8]
N-(pyridin-2-yl)pyrimidin-4-amine derivative 2	DMTZ6K9	N. A.	N. A.	Patented	[8]
N-phenyl-pyrimidin-4-amine derivative 1	DMAV8LM	N. A.	N. A.	Patented	[8]
Nitrogen mustard derivative 1	DMXDSYU	N. A.	N. A.	Patented	[8]
Oxazolyl methylthiothiazole derivative 1	DMZM6FW	N. A.	N. A.	Patented	[8]
Phenylpyridine derivative 1	DMVHLQM	N. A.	N. A.	Patented	[8]
Phenylpyridine derivative 2	DMTRPE6	N. A.	N. A.	Patented	[8]
PMID26161698-Compound-25	DM4AFHY	N. A.	N. A.	Patented	[8]
PMID26161698-Compound-32	DMRIWKV	N. A.	N. A.	Patented	[8]
Pyrazinylpyridine derivative 1	DMUXQST	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]-1,3,5-triazine derivative 1	DMOK7CW	N. A.	N. A.	Patented	[8]
Roscovitine derivative 1	DMD1G3Z	N. A.	N. A.	Patented	[8]
Tricyclic benzimidazole derivative 1	DM5SD9E	N. A.	N. A.	Patented	[8]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SCH 727965	DMCJLD1	Acute lymphoblastic leukaemia	2A85	Discontinued in Phase 3	[1]
BAY 10-00394	DMV2DIW	Small-cell lung cancer	2C25.Y	Discontinued in Phase 2	[9]
ZK 304709	DMJ9R4A	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[1]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
NVP-2	DMO5EXL	Solid tumour/cancer	2A00-2F9Z	Preclinical	[10]

14 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol	DMJZK40	Discovery agent	N.A.	Investigative	[11]
4-(phenyldiazenyl)-1H-pyrazole-3,5-diamine	DM54MOP	Discovery agent	N.A.	Investigative	[11]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[11]
Deschloroflavopiridol	DMQER8D	Discovery agent	N.A.	Investigative	[12]
MERIOLIN 1	DMJT93H	Discovery agent	N.A.	Investigative	[13]
MERIOLIN 2	DM413XJ	Discovery agent	N.A.	Investigative	[13]
MERIOLIN 3	DMVE95S	Discovery agent	N.A.	Investigative	[13]
MERIOLIN 4	DMIJMZQ	Discovery agent	N.A.	Investigative	[13]
MERIOLIN 5	DMGVLR0	Discovery agent	N.A.	Investigative	[13]
MERIOLIN 6	DMW5AXC	Discovery agent	N.A.	Investigative	[13]
MERIOLIN 7	DM8D3NY	Discovery agent	N.A.	Investigative	[13]
MERIOLIN 8	DM0E95B	Discovery agent	N.A.	Investigative	[13]
PMID19115845C89S	DMB9F2L	Discovery agent	N.A.	Investigative	[14]
PMID20873740C18	DMVHR3Z	Discovery agent	N.A.	Investigative	[15]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	4.38E-01	-0.04	-0.1
Breast cancer	2C82	Breast tissue	7.49E-37	-0.49	-1.07

References

• [1] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Clinical pipeline report, company report or official report of BioTheryX.
• [4] 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.
• [5] Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2009 May 7;113(19):4637-45.
• [6] Development of cell-cycle inhibitors for cancer therapy. Curr Oncol. 2009 Mar;16(2):36-43.
• [7] Clinical pipeline report, company report or official report of Sumitomo Dainippon Pharma.
• [8] Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.
• [9] National Cancer Institute Drug Dictionary (drug id 770319).
• [10] 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. (Target id: 1981).
• [11] 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.
• [12] Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci. 2002 Sep;23(9):417-25.
• [13] 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.
• [14] 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.
• [15] 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.