checkpoint kinase 2 | RAD53 family | IUPHAR/BPS Guide to PHARMACOLOGY

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checkpoint kinase 2

Target not currently curated in GtoImmuPdb

Target id: 1988

Nomenclature: checkpoint kinase 2

Abbreviated Name: Chk2

Family: RAD53 family, CHK1 subfamily

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 586 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
CDS1 | HuCds1 | PP1425 | RAD53
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
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
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
Chk2 inhibitor II Hs Inhibition 7.4 pKi 6
pKi 7.4 (Ki 3.7x10-8 M) [6]
CCT241533 Hs Inhibition 8.5 pIC50 2
pIC50 8.5 (IC50 3x10-9 M) [2]
prexasertib Hs Inhibition 8.1 pIC50 10
pIC50 8.1 (IC50 8x10-9 M) [10]
Description: Enzyme assay
AZD7762 Hs Inhibition >8.0 pIC50 13
pIC50 >8.0 (IC50 <1x10-8 M) [13]
compound 25b [PMID: 22564207] Hs Inhibition 7.5 pIC50 8
pIC50 7.5 (IC50 2.9x10-8 M) [8]
PF-477736 Hs Inhibition 7.3 pIC50 3
pIC50 7.3 (IC50 4.7x10-8 M) [3]
CDK inhibitor 4.35 Hs Inhibition 6.3 pIC50 9
pIC50 6.3 (IC50 5.25x10-7 M) [9]
7-hydroxystaurosporine Hs Inhibition 6.0 pIC50 4
pIC50 6.0 (IC50 1.04x10-6 M) [4]
CCT245737 Hs Inhibition 5.6 pIC50 12
pIC50 5.6 (IC50 2.44x10-6 M) [12]
isogranulatimide Hs Inhibition 5.5 pIC50 6
pIC50 5.5 (IC50 3x10-6 M) [6]
DiscoveRx KINOMEscan® screen
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 Hs Inhibitor Inhibition 8.0 pKd
SU-14813 Hs Inhibitor Inhibition 7.4 pKd
foretinib Hs Inhibitor Inhibition 7.2 pKd
NVP-TAE684 Hs Inhibitor Inhibition 7.1 pKd
staurosporine Hs Inhibitor Inhibition 7.1 pKd
KW-2449 Hs Inhibitor Inhibition 7.0 pKd
bosutinib Hs Inhibitor Inhibition 6.9 pKd
lestaurtinib Hs Inhibitor Inhibition 6.7 pKd
GSK-1838705A Hs Inhibitor Inhibition 6.6 pKd
AST-487 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
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 Hs Inhibitor Inhibition 0.7 2.0 1.0
Syk inhibitor Hs Inhibitor Inhibition 1.3 4.0 1.0
staurosporine Hs Inhibitor Inhibition 1.3 3.0 0.5
Chk2 inhibitor II Hs Inhibitor Inhibition 1.4 0.0 0.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 2.0 4.0 0.0
K-252a Hs Inhibitor Inhibition 2.9 3.0 1.0
SU11652 Hs Inhibitor Inhibition 6.4 6.0 1.0
sunitinib Hs Inhibitor Inhibition 7.1
alsterpaullone Hs Inhibitor Inhibition 7.9 3.0 1.0
Syk inhibitor II 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
Disease:  Breast cancer
Disease Ontology: DOID:1612
OMIM: 114480
Comments: 
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. U.S.A., 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, Havlicek L, Sturc A, Tuskova D, Daumova L, Alam M, Skerlova J, Nekardova M, Perina M, Pospíšil T et al.. (2019) 3,5,7-Substituted pyrazolo[4,3-d]pyrimidine inhibitors of cyclindependent kinases and their evaluation in lymphoma models. Journal of Medicinal Chemistry, Just Accepted Manuscript. DOI: 10.1021/acs.jmedchem.9b00189

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 19/06/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1988.