Target General Infomation
Target ID
T28713 (Former ID: TTDC00010)
Target Name
Serine/threonine-protein kinase Chk2 (RAD53)
Synonyms
hCds1; Hucds1; Checkpoint kinase 2; Cds1 homolog; Cds1; CHK2 checkpoint homolog; CHK2
Gene Name
CHEK2
Target Type
Clinical trial target
[1]
Disease [+] 1 Target-related Diseases +
1 Solid tumour/cancer [ICD-11: 2A00-2F9Z]
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.
BioChemical Class
Kinase
UniProt ID
CHK2_HUMAN
EC Number
EC 2.7.11.1
Sequence
MSRESDVEAQQSHGSSACSQPHGSVTQSQGSSSQSQGISSSSTSTMPNSSQSSHSSSGTL
SSLETVSTQELYSIPEDQEPEDQEPEEPTPAPWARLWALQDGFANLECVNDNYWFGRDKS
CEYCFDEPLLKRTDKYRTYSKKHFRIFREVGPKNSYIAYIEDHSGNGTFVNTELVGKGKR
RPLNNNSEIALSLSRNKVFVFFDLTVDDQSVYPKALRDEYIMSKTLGSGACGEVKLAFER
KTCKKVAIKIISKRKFAIGSAREADPALNVETEIEILKKLNHPCIIKIKNFFDAEDYYIV
LELMEGGELFDKVVGNKRLKEATCKLYFYQMLLAVQYLHENGIIHRDLKPENVLLSSQEE
DCLIKITDFGHSKILGETSLMRTLCGTPTYLAPEVLVSVGTAGYNRAVDCWSLGVILFIC
LSGYPPFSEHRTQVSLKDQITSGKYNFIPEVWAEVSEKALDLVKKLLVVDPKARFTTEEA
LRHPWLQDEDMKRKFQDLLSEENESTALPQVLAQPSTSRKRPREGEAEGAETTKRPAVCA
AVL
Drugs and Modes of Action
Clinical Trial Drug(s) [+] 1 Clinical Trial Drugs +
1 E7850 Drug Info Phase 2 Solid tumour/cancer [2], [3]
Discontinued Drug(s) [+] 1 Discontinued Drugs +
1 XL844 Drug Info Discontinued in Phase 1 Solid tumour/cancer [4]
Mode of Action [+] 2 Modes of Action +
Modulator [+] 2 Modulator drugs +
1 E7850 Drug Info [1]
2 XL844 Drug Info [6]
Inhibitor [+] 8 Inhibitor drugs +
1 PMID27410995-Compound-Figure3j Drug Info [5]
2 2-(4-Phenoxy-phenyl)-1H-benzoimidazol-5-ylamine Drug Info [7]
3 5-Nitro-2-(4-phenoxy-phenyl)-1H-benzoimidazole Drug Info [7]
4 CCT-241533 Drug Info [8]
5 Chk2 inhibitor II Drug Info [9]
6 DEBROMOHYMENIALDISINE Drug Info [10]
7 PMID22564207C25b Drug Info [11]
8 PV-1019 Drug Info [12]
Target Regulators
Target-regulating microRNAs
Target-interacting Proteins
Target Affiliated Biological Pathways
KEGG Pathway [+] 3 KEGG Pathways +
1 Cell cycle
2 p53 signaling pathway
3 HTLV-I infection
PID Pathway [+] 4 PID Pathways +
1 ATM pathway
2 FOXM1 transcription factor network
3 p53 pathway
4 PLK3 signaling events
Reactome [+] 3 Reactome Pathways +
1 Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
2 G2/M DNA damage checkpoint
3 Ubiquitin Mediated Degradation of Phosphorylated Cdc25A
WikiPathways [+] 8 WikiPathways +
1 DNA Damage Response
2 ATM Signaling Pathway
3 Integrated Pancreatic Cancer Pathway
4 Prostate Cancer
5 Integrated Breast Cancer Pathway
6 Integrated Cancer pathway
7 Cell Cycle
8 miRNA Regulation of DNA Damage Response
Target-Related Models and Studies
Target Validation
References
REF 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).
REF 2 Irofulven induces replication-dependent CHK2 activation related to p53 status. Biochem Pharmacol. 2007 Feb 15;73(4):469-80.
REF 3 ATM-dependent CHK2 activation induced by anticancer agent, irofulven. J Biol Chem. 2004 Sep 17;279(38):39584-92.
REF 4 ClinicalTrials.gov (NCT00234481) Safety Study of XL844 in Subjects With Chronic Lymphocytic Leukemia. U.S. National Institutes of Health.
REF 5 Ribosomal S6 kinase (RSK) modulators: a patent review.Expert Opin Ther Pat. 2016 Sep;26(9):1061-78.
REF 6 Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
REF 7 Checkpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles. J Med Chem. 2005 Mar 24;48(6):1873-85.
REF 8 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.
REF 9 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.
REF 10 Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4319-21.
REF 11 Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase. J Med Chem. 2012 May 24;55(10):4580-93.
REF 12 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.

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Wang and Dr. Li.