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checkpoint kinase 2

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Target id: 1988

Nomenclature: checkpoint kinase 2

Abbreviated Name: Chk2

Family: RAD53 family, CHK1 subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 543 22q12.1 CHEK2 checkpoint kinase 2
Mouse - 546 5 F Chek2 checkpoint kinase 2
Rat - 545 12 q16 Chek2 checkpoint kinase 2
Previous and Unofficial Names Click here for help
CDS1 | HuCds1 | PP1425 | RAD53
Database Links Click here for help
Alphafold O96017 (Hs), Q9Z265 (Mm)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL2527 (Hs)
Ensembl Gene ENSG00000183765 (Hs), ENSMUSG00000029521 (Mm), ENSRNOG00000037509 (Rn)
Entrez Gene 11200 (Hs), 50883 (Mm), 114212 (Rn)
Human Protein Atlas ENSG00000183765 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:11200 (Hs), mmu:50883 (Mm), rno:114212 (Rn)
OMIM 604373 (Hs)
Orphanet ORPHA119394 (Hs)
Pharos O96017 (Hs)
RefSeq Nucleotide NM_001005735 (Hs), NM_016681 (Mm), NM_053677 (Rn)
RefSeq Protein NP_001005735 (Hs), NP_057890 (Mm), NP_446129 (Rn)
UniProtKB O96017 (Hs), Q9Z265 (Mm)
Wikipedia CHEK2 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH ADP
PDB Id:  2CN5
Ligand:  ADP   This ligand is endogenous
Resolution:  2.25Å
Species:  Human
References:  11
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
Chk2 inhibitor II Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 7.4 pKi 6
⤷ pKi 7.4 (Ki 3.7x10-8 M) [6]
CCT241533 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.5 pIC50 2
⤷ pIC50 8.5 (IC50 3x10-9 M) [2]
prexasertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.1 pIC50 10
⤷ pIC50 8.1 (IC50 8x10-9 M) [10]
Description: Enzyme assay
AZD7762 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition >8.0 pIC50 13
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [13]
compound 25b [PMID: 22564207] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.5 pIC50 8
⤷ pIC50 7.5 (IC50 2.9x10-8 M) [8]
PF-477736 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.3 pIC50 3
⤷ pIC50 7.3 (IC50 4.7x10-8 M) [3]
CDK inhibitor 4.35 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.3 pIC50 9
⤷ pIC50 6.3 (IC50 5.25x10-7 M) [9]
7-hydroxystaurosporine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.0 pIC50 4
⤷ pIC50 6.0 (IC50 1.04x10-6 M) [4]
CCT245737 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.6 pIC50 12
⤷ pIC50 5.6 (IC50 2.44x10-6 M) [12]
isogranulatimide Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.5 pIC50 6
⤷ pIC50 5.5 (IC50 3x10-6 M) [6]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 5,14
Key to terms and symbols Click column headers to sort
Target used in screen: CHEK2
Ligand Sp. Type Action Value Parameter
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 8.0 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 7.4 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 7.0 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.9 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.7 pKd
GSK-1838705A Small molecule or natural product Hs Inhibitor Inhibition 6.6 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 6.4 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 1,7
Key to terms and symbols Click column headers to sort
Target used in screen: CHK2/CHK2
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.7 2.0 1.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.3 3.0 0.5
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 1.3 4.0 1.0
Chk2 inhibitor II Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.4 0.0 0.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.0 4.0 0.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 2.9 3.0 1.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 6.0 1.0
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.1
alsterpaullone Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.9 3.0 1.0
Syk inhibitor II Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 11.5 15.0 2.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Breast cancer
Disease Ontology: DOID:1612
OMIM: 114480
Comments:  Mutations in CHEK2 cause increased susceptibility to breast cancer
Disease:  Familial prostate cancer
Synonyms: Prostate cancer [OMIM: 176807] [Disease Ontology: DOID:10283]
Disease Ontology: DOID:10283
OMIM: 176807
Orphanet: ORPHA1331
Disease:  Hereditary breast and ovarian cancer syndrome
Synonyms: Hereditary breast ovarian cancer [Disease Ontology: DOID:5683]
Disease Ontology: DOID:5683
Orphanet: ORPHA145
Disease:  Li-Fraumeni syndrome
Disease Ontology: DOID:3012
OMIM: 609265
Orphanet: ORPHA524
Disease:  Osteogenic sarcoma
Synonyms: Osteosarcoma [Orphanet: ORPHA668] [Disease Ontology: DOID:3347]
Disease Ontology: DOID:3347
OMIM: 259500
Orphanet: ORPHA668

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Anderson VE, Walton MI, Eve PD, Boxall KJ, Antoni L, Caldwell JJ, Aherne W, Pearl LH, Oliver AW, Collins I et al.. (2011) CCT241533 is a potent and selective inhibitor of CHK2 that potentiates the cytotoxicity of PARP inhibitors. Cancer Res, 71 (2): 463-72. [PMID:21239475]

3. Blasina A, Hallin J, Chen E, Arango ME, Kraynov E, Register J, Grant S, Ninkovic S, Chen P, Nichols T et al.. (2008) Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1. Mol Cancer Ther, 7 (8): 2394-404. [PMID:18723486]

4. Busby EC, Leistritz DF, Abraham RT, Karnitz LM, Sarkaria JN. (2000) The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1. Cancer Res, 60 (8): 2108-12. [PMID:10786669]

5. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

6. Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci USA, 104 (51): 20523-8. [PMID:18077363]

7. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

8. Gingrich DE, Lisko JG, Curry MA, Cheng M, Quail M, Lu L, Wan W, Albom MS, Angeles TS, Aimone LD et al.. (2012) Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase. J Med Chem, 55 (10): 4580-93. [PMID:22564207]

9. Jorda R, Havlíček L, Šturc A, Tušková D, Daumová L, Alam M, Škerlová J, Nekardová M, Peřina M, Pospíšil T et al.. (2019) 3,5,7-Substituted Pyrazolo[4,3- d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models. J Med Chem, 62 (9): 4606-4623. DOI: 10.1021/acs.jmedchem.9b00189 [PMID:30943029]

10. King C, Diaz HB, McNeely S, Barnard D, Dempsey J, Blosser W, Beckmann R, Barda D, Marshall MS. (2015) LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Mol Cancer Ther, 14 (9): 2004-13. [PMID:26141948]

11. Oliver AW, Paul A, Boxall KJ, Barrie SE, Aherne GW, Garrett MD, Mittnacht S, Pearl LH. (2006) Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange. EMBO J, 25 (13): 3179-90. [PMID:16794575]

12. Osborne JD, Matthews TP, McHardy T, Proisy N, Cheung KM, Lainchbury M, Brown N, Walton MI, Eve PD, Boxall KJ et al.. (2016) Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737). J Med Chem, 59 (11): 5221-37. [PMID:27167172]

13. Oza V, Ashwell S, Almeida L, Brassil P, Breed J, Deng C, Gero T, Grondine M, Horn C, Ioannidis S et al.. (2012) Discovery of checkpoint kinase inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by structure-based design and optimization of thiophenecarboxamide ureas. J Med Chem, 55 (11): 5130-42. [PMID:22551018]

14. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

How to cite this page

RAD53 family: checkpoint kinase 2. Last modified on 05/04/2019. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1988.