Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT9ABMF)

• DTT Name: Serine/threonine-protein kinase Chk2 (RAD53)
• Synonyms: hCds1; Hucds1; Checkpoint kinase 2; Cds1 homolog; Cds1; CHK2 checkpoint homolog; CHK2
• Gene Name: CHEK2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: CHK2_HUMAN
• TTD ID: T28713
• EC Number: EC 2.7.11.1
• Sequence:
  MSRESDVEAQQSHGSSACSQPHGSVTQSQGSSSQSQGISSSSTSTMPNSSQSSHSSSGTL
  SSLETVSTQELYSIPEDQEPEDQEPEEPTPAPWARLWALQDGFANLECVNDNYWFGRDKS
  CEYCFDEPLLKRTDKYRTYSKKHFRIFREVGPKNSYIAYIEDHSGNGTFVNTELVGKGKR
  RPLNNNSEIALSLSRNKVFVFFDLTVDDQSVYPKALRDEYIMSKTLGSGACGEVKLAFER
  KTCKKVAIKIISKRKFAIGSAREADPALNVETEIEILKKLNHPCIIKIKNFFDAEDYYIV
  LELMEGGELFDKVVGNKRLKEATCKLYFYQMLLAVQYLHENGIIHRDLKPENVLLSSQEE
  DCLIKITDFGHSKILGETSLMRTLCGTPTYLAPEVLVSVGTAGYNRAVDCWSLGVILFIC
  LSGYPPFSEHRTQVSLKDQITSGKYNFIPEVWAEVSEKALDLVKKLLVVDPKARFTTEEA
  LRHPWLQDEDMKRKFQDLLSEENESTALPQVLAQPSTSRKRPREGEAEGAETTKRPAVCA
  AVL
• Function: May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells. Promotes the CCAR2-SIRT1 association and is required for CCAR2-mediated SIRT1 inhibition. Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks.
• KEGG Pathway:
  Cell cycle (hsa04110)
  p53 signaling pathway (hsa04115)
  HTLV-I infection (hsa05166)
• Reactome Pathway:
  G2/M DNA damage checkpoint (R-HSA-69473)
  Ubiquitin Mediated Degradation of Phosphorylated Cdc25A (R-HSA-69601)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)

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
E7850	DM8K5IF	Solid tumour/cancer	2A00-2F9Z	Phase 2	[1]

1 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID27410995-Compound-Figure3j	DMJRZLB	N. A.	N. A.	Patented	[2]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
XL844	DMHTG38	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[3]

7 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(4-Phenoxy-phenyl)-1H-benzoimidazol-5-ylamine	DMSPOAT	Discovery agent	N.A.	Investigative	[4]
5-Nitro-2-(4-phenoxy-phenyl)-1H-benzoimidazole	DM26MIC	Discovery agent	N.A.	Investigative	[4]
CCT-241533	DMZXFT9	Solid tumour/cancer	2A00-2F9Z	Investigative	[5]
Chk2 inhibitor II	DMNSPFG	Discovery agent	N.A.	Investigative	[6]
DEBROMOHYMENIALDISINE	DMDLER8	Discovery agent	N.A.	Investigative	[7]
PMID22564207C25b	DMBMYKQ	Discovery agent	N.A.	Investigative	[8]
PV-1019	DMRI1LF	Solid tumour/cancer	2A00-2F9Z	Investigative	[9]

References

• [1] 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: 1988).
• [2] Ribosomal S6 kinase (RSK) modulators: a patent review.Expert Opin Ther Pat. 2016 Sep;26(9):1061-78.
• [3] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [4] Checkpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles. J Med Chem. 2005 Mar 24;48(6):1873-85.
• [5] CCT241533 Is a Potent and Selective Inhibitor of CHK2 that Potentiates the Cytotoxicity of PARP Inhibitors. Cancer Res. 2011 Jan 15;71(2):463-72.
• [6] 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.
• [7] Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4319-21.
• [8] Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase. J Med Chem. 2012 May 24;55(10):4580-93.
• [9] Cellular inhibition of checkpoint kinase 2 (Chk2) and potentiation of camptothecins and radiation by the novel Chk2 inhibitor PV1019 [7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide]. J Pharmacol Exp Ther. 2009 Dec;331(3):816-26.