Target Information

Target General Infomation
Target ID
T62449
Former ID
TTDC00005
Target Name
Serine/threonine-protein kinase Chk1
Gene Name
CHEK1
Synonyms
Chk1; CHEK1
Target Type
Clinical Trial
Disease Advanced solid tumor [ICD9: 140-199; ICD10: C00-C75, C7A, C7B]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86]
Non-small cell lung cancer [ICD10: C33-C34]
Non-small cell lung cancer; Pancreatic cancer [ICD9:140-199, 140-229, 157, 210-229; ICD10: C33-C34, C25]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Isoform 2: Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition.
BioChemical Class
Kinase
Target Validation
T62449
UniProt ID
O14757
EC Number
EC 2.7.11.1
Sequence
MAVPFVEDWDLVQTLGEGAYGEVQLAVNRVTEEAVAVKIVDMKRAVDCPENIKKEICINK
MLNHENVVKFYGHRREGNIQYLFLEYCSGGELFDRIEPDIGMPEPDAQRFFHQLMAGVVY
LHGIGITHRDIKPENLLLDERDNLKISDFGLATVFRYNNRERLLNKMCGTLPYVAPELLK
RREFHAEPVDVWSCGIVLTAMLAGELPWDQPSDSCQEYSDWKEKKTYLNPWKKIDSAPLA
LLHKILVENPSARITIPDIKKDRWYNKPLKKGAKRPRVTSGGVSESPSGFSKHIQSNLDF
SPVNSASSEENVKYSSSQPEPRTGLSLWDTSPSYIDKLVQGISFSQPTCPDHMLLNSQLL
GTPGSSQNPWQRLVKRMTRFFTKLDADKSYQCLKETCEKLGYQWKKSCMNQVTISTTDRR
NNKLIFKVNLLEMDDKILVDFRLSKGDGLEFKRHFLKIKGKLIDIVSSQKIWLPAT
Drugs and Mode of Action
Drug(s) CI-1040 Drug Info Phase 2 Discovery agent [521505], [541019]
LY2603618 Drug Info Phase 2 Non-small cell lung cancer; Pancreatic cancer [522807], [542877]
SCH-900776 Drug Info Phase 2 Cancer [524312], [542858]
UCN-01 Drug Info Phase 2 Non-small cell lung cancer [521597]
AZD7762 Drug Info Phase 1 Solid tumours [522029], [542688]
GDC-0425 Drug Info Phase 1 Lymphoma [523494]
LY2606368 MsOH H2O Drug Info Phase 1 Cancer [551090]
RG7741 Drug Info Phase 1 Lymphoma [549233]
PF-477736 Drug Info Discontinued in Phase 1 Advanced solid tumor [542941], [548144]
RG7602 Drug Info Discontinued in Phase 1 Lymphoma [549282]
XL844 Drug Info Discontinued in Phase 1 Solid tumours [521743]
Inhibitor 2-(cyclohexylamino)benzoic acid Drug Info [551374]
3-(1H-BENZIMIDAZOL-2-YL)-1H-INDAZOLE Drug Info [551374]
3-(1H-Indol-2-yl)-1H-quinolin-2-one Drug Info [528445]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole Drug Info [527308]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol Drug Info [528490]
6-(3-aminopropyl)benzo[h]isoquinolin-1(2H)-one Drug Info [529069]
6-MORPHOLIN-4-YL-9H-PURINE Drug Info [551374]
9-chlorobenzo[h]isoquinolin-1(2H)-one Drug Info [529069]
9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione Drug Info [528350]
A-432411 Drug Info [531069]
ARRY-575 Drug Info [543531]
AZD7762 Drug Info [550288]
BIS-IMIDE A Drug Info [528838]
BX-795 Drug Info [527484]
BX-912 Drug Info [527484]
CCT244747 Drug Info [532088]
Chk1-A Drug Info [543531]
CI-1040 Drug Info [525872]
compound 25 Drug Info [529100]
compound 25 Drug Info [531168]
compound 33 Drug Info [530078]
DEBROMOHYMENIALDISINE Drug Info [527140]
GF-109203 Drug Info [525872]
GRANULATIMIDE Drug Info [528838]
ISOGRANULATIMIDE Drug Info [528838]
KN-62 Drug Info [525872]
N-(5,6-DIPHENYLFURO[2,3-D]PYRIMIDIN-4-YL)GLYCINE Drug Info [551374]
NU-6102 Drug Info [527906]
PF-477736 Drug Info [537564]
RO-316233 Drug Info [525872]
S-024 Drug Info [543531]
S-070 Drug Info [543531]
SB 218078 Drug Info [525695]
SCH-900776 Drug Info [531364]
UCN-01 Drug Info [535584], [537127], [537231], [537385], [537458]
Modulator GDC-0425 Drug Info [549773]
LY2603618 Drug Info [532505]
LY2606368 MsOH H2O Drug Info [543531]
RG7602 Drug Info [550475]
RG7741 Drug Info [544397], [550488]
XL844 Drug Info [1572591]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Cell cycle
p53 signaling pathway
HTLV-I infection
Viral carcinogenesis
Pathway Interaction Database Fanconi anemia pathway
p73 transcription factor network
ATR signaling pathway
Circadian rhythm pathway
p53 pathway
Reactome Activation of ATR in response to replication stress
Processing of DNA double-strand break ends
Presynaptic phase of homologous DNA pairing and strand exchange
G2/M DNA damage checkpoint
Ubiquitin Mediated Degradation of Phosphorylated Cdc25A
Cdk1 complex
WikiPathways DNA Damage Response
Signaling by SCF-KIT
ATM Signaling Pathway
Retinoblastoma (RB) in Cancer
Integrated Pancreatic Cancer Pathway
Prostate Cancer
Integrated Breast Cancer Pathway
Integrated Cancer pathway
Cell Cycle
Cell Cycle Checkpoints
miRNA Regulation of DNA Damage Response
References
Ref 521505ClinicalTrials.gov (NCT00033384) CI-1040 in Treating Patients With Advanced Breast, Colon, Pancreatic, or Non-Small Cell Lung Cancer. U.S. National Institutes of Health.
Ref 521597ClinicalTrials.gov (NCT00082017) UCN-01 (7-Hydroxystaurosporine) to Treat Relapsed T-Cell Lymphomas. U.S. National Institutes of Health.
Ref 521743ClinicalTrials.gov (NCT00234481) Safety Study of XL844 in Subjects With Chronic Lymphocytic Leukemia. U.S. National Institutes of Health.
Ref 522029ClinicalTrials.gov (NCT00473616) Phase I Single Ascending Dose/Multiple Ascending Dose in Patients Treated With AZD7762 and Irinotecan. U.S. National Institutes of Health.
Ref 522807ClinicalTrials.gov (NCT00988858) A Study of Advanced or Metastatic Non-small Cell Lung Cancer. U.S. National Institutes of Health.
Ref 523494ClinicalTrials.gov (NCT01359696) A Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GDC-0425 Administered With and Without Gemcitabine in Patients With Refractory Solid Tumors or Lymphoma. U.S. National Institutes of Health.
Ref 524312ClinicalTrials.gov (NCT01870596) Cytarabine With or Without SCH 900776 in Treating Adult Patients With Relapsed Acute Myeloid Leukemia. U.S. National Institutes of Health.
Ref 541019(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. (Ligand id: 5676).
Ref 542688(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. (Ligand id: 7713).
Ref 542858(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. (Ligand id: 7943).
Ref 542877(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. (Ligand id: 7960).
Ref 542941(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. (Ligand id: 8043).
Ref 548144Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022394)
Ref 549233Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034037)
Ref 549282Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034639)
Ref 551090Clinical pipeline report, company report or official report of Eli Lilly.
Ref
Ref 525695An indolocarbazole inhibitor of human checkpoint kinase (Chk1) abrogates cell cycle arrest caused by DNA damage. Cancer Res. 2000 Feb 1;60(3):566-72.
Ref 525872Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors.
Ref 527140Bioorg Med Chem Lett. 2004 Aug 16;14(16):4319-21.Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine.
Ref 527308J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole.
Ref 527484Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2005 May 20;280(20):19867-74. Epub 2005 Mar 16.
Ref 527906Bioorg Med Chem Lett. 2006 Mar 1;16(5):1353-7. Epub 2005 Dec 1.Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: protein structure-guided design and SAR.
Ref 528350J Med Chem. 2006 Aug 10;49(16):4896-911.4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione inhibitors of the checkpoint kinase Wee1. Structure-activity relationships for chromophore modification and phenyl ring substitution.
Ref 528445Bioorg Med Chem Lett. 2006 Nov 15;16(22):5907-12. Epub 2006 Sep 20.Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors.
Ref 528490J Med Chem. 2006 Nov 2;49(22):6500-9.4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
Ref 528838Eur J Med Chem. 2008 Feb;43(2):282-92. Epub 2007 Apr 7.Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of pyrrolo[3,4-a]carbazole-1,3-diones, pyrrolo[3,4-c]carbazole-1,3-diones, and 2-aminopyridazino[3,4-a]pyrrolo[3,4-c]carbazole-1,3,4,7-tetraone.
Ref 529069Bioorg Med Chem Lett. 2007 Nov 15;17(22):6280-5. Epub 2007 Sep 7.Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase.
Ref 529100Macrocyclic ureas as potent and selective Chk1 inhibitors: an improved synthesis, kinome profiling, structure-activity relationships, and preliminary pharmacokinetics. Bioorg Med Chem Lett. 2007 Dec 1;17(23):6593-601. Epub 2007 Sep 22.
Ref 530078Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg Med Chem. 2009 May 1;17(9):3342-51.
Ref 531069Bioorg Med Chem Lett. 2010 Sep 1;20(17):5065-8. Epub 2010 Jul 13.Synthesis of selenophene derivatives as novel CHK1 inhibitors.
Ref 531168Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6739-43.
Ref 531364Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol Cancer Ther. 2011 Apr;10(4):591-602.
Ref 532088Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors. J Med Chem. 2012 Nov 26;55(22):10229-40.
Ref 532505Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs. 2014 Apr;32(2):213-26.
Ref 535584UCN-01 inhibits p53 up-regulation and abrogates gamma-radiation-induced G(2)-M checkpoint independently of p53 by targeting both of the checkpoint kinases, Chk2 and Chk1. Cancer Res. 2002 Oct 15;62(20):5743-8.
Ref 537127Cyclin-dependent kinase inhibitors as potential targeted anticancer agents. Invest New Drugs. 2009 Mar 5.
Ref 537231CHK1 inhibition as a strategy for targeting Fanconi Anemia (FA) DNA repair pathway deficient tumors. Mol Cancer. 2009 Apr 16;8:24.
Ref 537385Characterization of an inhibitory dynamic pharmacophore for the ERCC1-XPA interaction using a combined molecular dynamics and virtual screening approach. J Mol Graph Model. 2009 May 3.
Ref 537458The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem. 2009 Jun;9(5):550-9.
Ref 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 543531(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: 1987).
Ref 544397Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anti-cancer therapies. Expert Opin Drug Discov. 2013 June; 8(6): 621-640.
Ref 549773Quantitative assessment of BCL-2:BIM complexes as a pharmacodynamic marker for venetoclax (ABT-199).
Ref 550288Clinical pipeline report, company report or official report of AstraZeneca (2009).
Ref 550475National Cancer Institute Drug Dictionary (drug id 701310).
Ref 550488National Cancer Institute Drug Dictionary (drug id 730054).
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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