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checkpoint kinase 1

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Target id: 1987

Nomenclature: checkpoint kinase 1

Abbreviated Name: Chk1

Family: CHK1 subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 476 11q24.2 CHEK1 checkpoint kinase 1
Mouse - 476 9 A4 Chek1 checkpoint kinase 1
Rat - 476 8q21 Chek1 checkpoint kinase 1
Database Links Click here for help
Alphafold O14757 (Hs), O35280 (Mm), Q91ZN7 (Rn)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL4630 (Hs)
Ensembl Gene ENSG00000149554 (Hs), ENSMUSG00000032113 (Mm), ENSRNOG00000031896 (Rn), ENSRNOG00000071217 (Rn)
Entrez Gene 1111 (Hs), 12649 (Mm), 140583 (Rn)
Human Protein Atlas ENSG00000149554 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:1111 (Hs), mmu:12649 (Mm), rno:140583 (Rn)
OMIM 603078 (Hs)
Pharos O14757 (Hs)
RefSeq Nucleotide NM_001114121 (Hs), NM_007691 (Mm), NM_080400 (Rn)
RefSeq Protein NP_001107593 (Hs), NP_031717 (Mm), NP_536325 (Rn)
SynPHARM 80208 (in complex with AZD7762)
UniProtKB O14757 (Hs), O35280 (Mm), Q91ZN7 (Rn)
Wikipedia CHEK1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  The 1.7 A Crystal structure of human cell cycle checkpoint kinase CHK1
PDB Id:  1IA8
Resolution:  1.7Å
Species:  Human
References:  6
Image of receptor 3D structure from RCSB PDB
Description:  X-Ray Crystal structure of compound 40 bound to human chk1 kinase domain
PDB Id:  4HYI
Resolution:  1.4Å
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
CHIR-124 Small molecule or natural product Hs Inhibition 9.5 pIC50 19
⤷ pIC50 9.5 (IC50 3.2x10-10 M) [19]
PF-477736 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 9.3 pIC50 4
⤷ pIC50 9.3 (IC50 4.9x10-10 M) [4]
prexasertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.1 pIC50 15
⤷ pIC50 9.1 (IC50 9x10-10 M) [15]
Description: Biochemical assay using purified enzyme.
CCT245737 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.9 pIC50 20
⤷ pIC50 8.9 (IC50 1.3x10-9 M) [20]
MK-8776 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.5 pIC50 16
⤷ pIC50 8.5 (IC50 3x10-9 M) [16]
compound 25 [PMID: 17935989] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.4 pIC50 23
⤷ pIC50 8.4 (IC50 4x10-9 M) [23]
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 8.3 pIC50 21
⤷ pIC50 8.3 (IC50 5x10-9 M) [21]
rabusertib Small molecule or natural product Primary target of this compound Hs Inhibition 8.1 pIC50 14
⤷ pIC50 8.1 (IC50 7x10-9 M) [14]
CCT244747 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.1 pIC50 17
⤷ pIC50 8.1 (IC50 7.7x10-9 M) [17]
SB 218078 Small molecule or natural product Primary target of this compound Hs Inhibition 7.8 pIC50 12
⤷ pIC50 7.8 (IC50 1.5x10-8 M) [12]
7-hydroxystaurosporine Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 – 8.1 pIC50 5,13,22
⤷ pIC50 7.5 – 8.1 (IC50 3.5x10-8 – 7x10-9 M) [5,13,22]
compound 33 [PMID: 19364658] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.1 pIC50 18
⤷ pIC50 7.1 (IC50 9x10-8 M) [18]
isogranulatimide Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.0 pIC50 7,13
⤷ pIC50 7.0 (IC50 1x10-7 M) [7,13]
compound 25 [PMID: 20855207] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.8 pIC50 3
⤷ pIC50 6.8 (IC50 1.4x10-7 M) [3]
CCT241533 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.7 pIC50 2
⤷ pIC50 6.7 (IC50 1.9x10-7 M) [2]
BX-795 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.3 pIC50 9
⤷ pIC50 6.3 (IC50 5.1x10-7 M) [9]
BX-912 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.1 pIC50 9
⤷ pIC50 6.1 (IC50 8.3x10-7 M) [9]
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: 8,24
Key to terms and symbols Click column headers to sort
Target used in screen: CHEK1
Ligand Sp. Type Action Value Parameter
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.6 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.5 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 8.0 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 pKd
ruboxistaurin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.2 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 5.9 pKd
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 5.9 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 5.9 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: 1,10
Key to terms and symbols Click column headers to sort
Target used in screen: CHK1/CHK1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.6 -1.0 -0.5
K-252a Small molecule or natural product Hs Inhibitor Inhibition 2.6 1.0 -1.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 3.6 25.0 20.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 6.0 10.0 3.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.0 2.0 0.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 15.1 24.0 3.0
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 19.5 16.0 7.0
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 22.9 37.0 24.0
isogranulatimide Small molecule or natural product Hs Inhibitor Inhibition 24.6 18.0 14.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 27.1 35.0 8.0
Displaying the top 10 most potent ligands  View all ligands in screen »

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. Belanger DB, Williams MJ, Curran PJ, Mandal AK, Meng Z, Rainka MP, Yu T, Shih NY, Siddiqui MA, Liu M et al.. (2010) Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Bioorg Med Chem Lett, 20 (22): 6739-43. [PMID:20855207]

4. 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]

5. 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]

6. Chen P, Luo C, Deng Y, Ryan K, Register J, Margosiak S, Tempczyk-Russell A, Nguyen B, Myers P, Lundgren K et al.. (2000) The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1: implications for Chk1 regulation. Cell, 100 (6): 681-92. [PMID:10761933]

7. Conchon E, Anizon F, Aboab B, Golsteyn RM, Léonce S, Pfeiffer B, Prudhomme M. (2008) Synthesis, checkpoint kinase 1 inhibitory properties and in vitro antiproliferative activities of new pyrrolocarbazoles. Bioorg Med Chem, 16 (8): 4419-30. [PMID:18321713]

8. 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]

9. Feldman RI, Wu JM, Polokoff MA, Kochanny MJ, Dinter H, Zhu D, Biroc SL, Alicke B, Bryant J, Yuan S et al.. (2005) Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem, 280 (20): 19867-74. [PMID:15772071]

10. 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]

11. Huang X, Cheng CC, Fischmann TO, Duca JS, Richards M, Tadikonda PK, Reddy PA, Zhao L, Siddiqui MA, Parry D et al.. (2013) Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors. Bioorg Med Chem Lett, 23 (9): 2590-4. [PMID:23535330]

12. Jackson JR, Gilmartin A, Imburgia C, Winkler JD, Marshall LA, Roshak A. (2000) An indolocarbazole inhibitor of human checkpoint kinase (Chk1) abrogates cell cycle arrest caused by DNA damage. Cancer Res, 60 (3): 566-72. [PMID:10676638]

13. Jiang X, Zhao B, Britton R, Lim LY, Leong D, Sanghera JS, Zhou BB, Piers E, Andersen RJ, Roberge M. (2004) Inhibition of Chk1 by the G2 DNA damage checkpoint inhibitor isogranulatimide. Mol Cancer Ther, 3 (10): 1221-7. [PMID:15486189]

14. King C, Diaz H, Barnard D, Barda D, Clawson D, Blosser W, Cox K, Guo S, Marshall M. (2014) Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs, 32 (2): 213-26. [PMID:24114124]

15. 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]

16. Labroli M, Paruch K, Dwyer MP, Alvarez C, Keertikar K, Poker C, Rossman R, Duca JS, Fischmann TO, Madison V et al.. (2011) Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 2. Bioorg Med Chem Lett, 21 (1): 471-4. [PMID:21094607]

17. Lainchbury M, Matthews TP, McHardy T, Boxall KJ, Walton MI, Eve PD, Hayes A, Valenti MR, de Haven Brandon AK, Box G et al.. (2012) Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors. J Med Chem, 55 (22): 10229-40. [PMID:23082860]

18. Lovering F, Kirincich S, Wang W, Combs K, Resnick L, Sabalski JE, Butera J, Liu J, Parris K, Telliez JB. (2009) Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg Med Chem, 17 (9): 3342-51. [PMID:19364658]

19. Ni ZJ, Barsanti P, Brammeier N, Diebes A, Poon DJ, Ng S, Pecchi S, Pfister K, Renhowe PA, Ramurthy S et al.. (2006) 4-(Aminoalkylamino)-3-benzimidazole-quinolinones as potent CHK-1 inhibitors. Bioorg Med Chem Lett, 16 (12): 3121-4. [PMID:16603354]

20. 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]

21. 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]

22. Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB. (2007) p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell, 11 (2): 175-89. [PMID:17292828]

23. Tao ZF, Chen Z, Bui MH, Kovar P, Johnson E, Bouska J, Zhang H, Rosenberg S, Sowin T, Lin NH. (2007) Macrocyclic ureas as potent and selective Chk1 inhibitors: an improved synthesis, kinome profiling, structure-activity relationships, and preliminary pharmacokinetics. Bioorg Med Chem Lett, 17 (23): 6593-601. [PMID:17935989]

24. 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

CHK1 subfamily: checkpoint kinase 1. Last modified on 21/04/2017. Accessed on 10/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1987.