Target Information
Target General Infomation | |||||
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Target ID |
T62449
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Former ID |
TTDC00005
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Target Name |
Serine/threonine-protein kinase Chk1
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Gene Name |
CHEK1
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Synonyms |
Chk1; CHEK1
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Target Type |
Clinical Trial
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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.
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BioChemical Class |
Kinase
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Target Validation |
T62449
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UniProt ID | |||||
EC Number |
EC 2.7.11.1
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Sequence |
MAVPFVEDWDLVQTLGEGAYGEVQLAVNRVTEEAVAVKIVDMKRAVDCPENIKKEICINK
MLNHENVVKFYGHRREGNIQYLFLEYCSGGELFDRIEPDIGMPEPDAQRFFHQLMAGVVY LHGIGITHRDIKPENLLLDERDNLKISDFGLATVFRYNNRERLLNKMCGTLPYVAPELLK RREFHAEPVDVWSCGIVLTAMLAGELPWDQPSDSCQEYSDWKEKKTYLNPWKKIDSAPLA LLHKILVENPSARITIPDIKKDRWYNKPLKKGAKRPRVTSGGVSESPSGFSKHIQSNLDF SPVNSASSEENVKYSSSQPEPRTGLSLWDTSPSYIDKLVQGISFSQPTCPDHMLLNSQLL GTPGSSQNPWQRLVKRMTRFFTKLDADKSYQCLKETCEKLGYQWKKSCMNQVTISTTDRR NNKLIFKVNLLEMDDKILVDFRLSKGDGLEFKRHFLKIKGKLIDIVSSQKIWLPAT |
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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 521505 | ClinicalTrials.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 521597 | ClinicalTrials.gov (NCT00082017) UCN-01 (7-Hydroxystaurosporine) to Treat Relapsed T-Cell Lymphomas. U.S. National Institutes of Health. | ||||
Ref 521743 | ClinicalTrials.gov (NCT00234481) Safety Study of XL844 in Subjects With Chronic Lymphocytic Leukemia. U.S. National Institutes of Health. | ||||
Ref 522029 | ClinicalTrials.gov (NCT00473616) Phase I Single Ascending Dose/Multiple Ascending Dose in Patients Treated With AZD7762 and Irinotecan. U.S. National Institutes of Health. | ||||
Ref 522807 | ClinicalTrials.gov (NCT00988858) A Study of Advanced or Metastatic Non-small Cell Lung Cancer. U.S. National Institutes of Health. | ||||
Ref 523494 | ClinicalTrials.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 524312 | ClinicalTrials.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 548144 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022394) | ||||
Ref 549233 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034037) | ||||
Ref 525695 | An 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 525872 | Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors. | ||||
Ref 527140 | Bioorg Med Chem Lett. 2004 Aug 16;14(16):4319-21.Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine. | ||||
Ref 527308 | J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. | ||||
Ref 527484 | Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2005 May 20;280(20):19867-74. Epub 2005 Mar 16. | ||||
Ref 527906 | Bioorg 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 528350 | J 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 528445 | Bioorg 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 528490 | J 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 528838 | Eur 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 529069 | Bioorg 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 529100 | Macrocyclic 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 530078 | Identification 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 531069 | Bioorg Med Chem Lett. 2010 Sep 1;20(17):5065-8. Epub 2010 Jul 13.Synthesis of selenophene derivatives as novel CHK1 inhibitors. | ||||
Ref 531168 | Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6739-43. | ||||
Ref 531364 | Targeting 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 532088 | Discovery 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 532505 | Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs. 2014 Apr;32(2):213-26. | ||||
Ref 535584 | UCN-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 537127 | Cyclin-dependent kinase inhibitors as potential targeted anticancer agents. Invest New Drugs. 2009 Mar 5. | ||||
Ref 537231 | CHK1 inhibition as a strategy for targeting Fanconi Anemia (FA) DNA repair pathway deficient tumors. Mol Cancer. 2009 Apr 16;8:24. | ||||
Ref 537385 | Characterization 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 537458 | The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem. 2009 Jun;9(5):550-9. | ||||
Ref 537564 | Cell 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 544397 | Structure-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 549773 | Quantitative assessment of BCL-2:BIM complexes as a pharmacodynamic marker for venetoclax (ABT-199). |
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