Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTER6YH)

• DTT Name: Casein kinase II alpha (CSNK2A1)
• Synonyms: Protein kinase CK2; Casein kinase II subunit alpha; CK2A1; CK II alpha; CK II
• Gene Name: CSNK2A1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: CSK21_HUMAN
• TTD ID: T51565
• EC Number: EC 2.7.11.1
• Sequence:
  MSGPVPSRARVYTDVNTHRPREYWDYESHVVEWGNQDDYQLVRKLGRGKYSEVFEAINIT
  NNEKVVVKILKPVKKKKIKREIKILENLRGGPNIITLADIVKDPVSRTPALVFEHVNNTD
  FKQLYQTLTDYDIRFYMYEILKALDYCHSMGIMHRDVKPHNVMIDHEHRKLRLIDWGLAE
  FYHPGQEYNVRVASRYFKGPELLVDYQMYDYSLDMWSLGCMLASMIFRKEPFFHGHDNYD
  QLVRIAKVLGTEDLYDYIDKYNIELDPRFNDILGRHSRKRWERFVHSENQHLVSPEALDF
  LDKLLRYDHQSRLTAREAMEHPYFYTVVKDQARMGSSSMPGGSTPVSSANMMSGISSVPT
  PSPLGPLAGSPVIAAANPLGMPVPAAAGAQQ
• Function: Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV. Phosphorylates PML at 'Ser-565' and primes it for ubiquitin-mediated degradation. Plays an important role in the circadian clock function by phosphorylating ARNTL/BMAL1 at 'Ser-90' which is pivotal for its interaction with CLOCK and which controls CLOCK nuclear entry. Phosphorylates CCAR2 at 'Thr-454' in gastric carcinoma tissue. Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine.
• KEGG Pathway:
  Ribosome biogenesis in eukaryotes (hsa03008)
  NF-kappa B signaling pathway (hsa04064)
  Wnt signaling pathway (hsa04310)
  Adherens junction (hsa04520)
  Tight junction (hsa04530)
  Measles (hsa05162)
  Herpes simplex infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
• Reactome Pathway: Condensation of Prometaphase Chromosomes (R-HSA-2514853)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CX-4945	DMWE7B9	Coronavirus infection	1D92	Phase 2	[1]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BALANOL	DMDLN9E	N. A.	N. A.	Terminated	[2]
EMODIN	DMAEDQG	Coronavirus Disease 2019 (COVID-19)	1D6Y	Terminated	[3]

14 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4,5,6,7-tetrabromo-1H-benzimidazole	DMUE4K3	Discovery agent	N.A.	Investigative	[4]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[3]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[5]
5,6,8-trichloroquinoline-4-one-3-carboxylic acid	DMDCE1M	Discovery agent	N.A.	Investigative	[6]
5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole	DM3JB6S	Discovery agent	N.A.	Investigative	[3]
7,8-dichloroquinoline-4-one-3-carboxylic acid	DMKNQW4	Discovery agent	N.A.	Investigative	[6]
AdoC(Dpr)2AlaArg6	DM2TWSZ	Discovery agent	N.A.	Investigative	[7]
APIGENIN	DMI3491	Discovery agent	N.A.	Investigative	[3]
CGP-029482	DMNUQAG	Discovery agent	N.A.	Investigative	[3]
CX-5011	DMXD1IN	Solid tumour/cancer	2A00-2F9Z	Investigative	[8]
CX-7000	DMNTAV8	Solid tumour/cancer	2A00-2F9Z	Investigative	[8]
ELLAGIC ACID	DMX8BS5	Discovery agent	N.A.	Investigative	[3]
PMID22115617C2c	DMX5UKA	Discovery agent	N.A.	Investigative	[9]
PMID24900749C1a	DMZPUSO	Discovery agent	N.A.	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rectal cancer	2C82	Rectal colon tissue	6.82E-04	0.29	2.43

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Synthesis and protein kinase C inhibitory activities of acyclic balanol analogs that are highly selective for protein kinase C over protein kinase A. J Med Chem. 1996 Dec 20;39(26):5215-27.
• [3] Structural insight into human CK2alpha in complex with the potent inhibitor ellagic acid. Bioorg Med Chem Lett. 2009 Jun 1;19(11):2920-3.
• [4] Synthesis of new analogs of benzotriazole, benzimidazole and phthalimide--potential inhibitors of human protein kinase CK2. Bioorg Med Chem. 2009 Feb 15;17(4):1573-8.
• [5] 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.
• [6] Evaluation of 3-carboxy-4(1H)-quinolones as inhibitors of human protein kinase CK2. J Med Chem. 2006 Nov 2;49(22):6443-50.
• [7] Adenosine-5'-carboxylic acid peptidyl derivatives as inhibitors of protein kinases. Bioorg Med Chem Lett. 1999 May 17;9(10):1447-52.
• [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. (Target id: 1549).
• [9] CK2alpha and CK2alpha' subunits differ in their sensitivity to 4,5,6,7-tetrabromo- and 4,5,6,7-tetraiodo-1H-benzimidazole derivatives. Eur J Med Chem. 2012 Jan;47(1):345-50.
• [10] Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo. ACS Med Chem Lett. 2013 Jul 3;4(8):800-5.