Target Information
| Target General Information | Top | |||||
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| Target ID |
T62449
(Former ID: TTDC00005)
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| Target Name |
Checkpoint kinase-1 (CHK1)
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| Synonyms |
Serine/threonine-protein kinase Chk1; Chk1; Cell cycle checkpoint kinase; CHK1 checkpoint homolog
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| Gene Name |
CHEK1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 8 Target-related Diseases | + | ||||
| 1 | Lung cancer [ICD-11: 2C25] | |||||
| 2 | Ovarian cancer [ICD-11: 2C73] | |||||
| 3 | Pancreatic cancer [ICD-11: 2C10] | |||||
| 4 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| 5 | Anal cancer [ICD-11: 2C00] | |||||
| 6 | Head and neck cancer [ICD-11: 2D42] | |||||
| 7 | Hodgkin lymphoma [ICD-11: 2B30] | |||||
| 8 | Lymphoma [ICD-11: 2A80-2A86] | |||||
| Function |
May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. Phosphorylates histone H3. 1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest. Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA.
Click to Show/Hide
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| BioChemical Class |
Kinase
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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 Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T11BL5 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 9 Clinical Trial Drugs | + | ||||
| 1 | LY2603618 | Drug Info | Phase 2 | Pancreatic cancer | [2], [3] | |
| 2 | LY2606368 | Drug Info | Phase 2 | Ovarian cancer | [4] | |
| 3 | SCH-900776 | Drug Info | Phase 2 | Solid tumour/cancer | [5], [6] | |
| 4 | UCN-01 | Drug Info | Phase 2 | Non-small-cell lung cancer | [7] | |
| 5 | LY2880070 | Drug Info | Phase 1/2 | Solid tumour/cancer | [8] | |
| 6 | AZD7762 | Drug Info | Phase 1 | Solid tumour/cancer | [9], [10] | |
| 7 | GDC-0425 | Drug Info | Phase 1 | Lymphoma | [11] | |
| 8 | MK-8776 | Drug Info | Phase 1 | Hodgkin lymphoma | [12] | |
| 9 | RG7741 | Drug Info | Phase 1 | Lymphoma | [13] | |
| Discontinued Drug(s) | [+] 3 Discontinued Drugs | + | ||||
| 1 | PF-477736 | Drug Info | Discontinued in Phase 1 | Advanced solid tumour | [14], [15] | |
| 2 | RG7602 | Drug Info | Discontinued in Phase 1 | Lymphoma | [16] | |
| 3 | XL844 | Drug Info | Discontinued in Phase 1 | Solid tumour/cancer | [17] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 5 Modulator drugs | + | ||||
| 1 | LY2603618 | Drug Info | [18] | |||
| 2 | GDC-0425 | Drug Info | [27] | |||
| 3 | RG7741 | Drug Info | [29], [30] | |||
| 4 | RG7602 | Drug Info | [33] | |||
| 5 | XL844 | Drug Info | [34] | |||
| Inhibitor | [+] 41 Inhibitor drugs | + | ||||
| 1 | LY2606368 | Drug Info | [4], [19] | |||
| 2 | SCH-900776 | Drug Info | [20] | |||
| 3 | UCN-01 | Drug Info | [1], [21], [22], [23], [24] | |||
| 4 | LY2880070 | Drug Info | [25] | |||
| 5 | AZD7762 | Drug Info | [26] | |||
| 6 | MK-8776 | Drug Info | [28] | |||
| 7 | Diamidothiazole derivative 1 | Drug Info | [31] | |||
| 8 | PF-477736 | Drug Info | [32] | |||
| 9 | 2-(1H-indazol-3-yl)-1H-benzo[d]imidazole | Drug Info | [35] | |||
| 10 | 2-(cyclohexylamino)benzoic acid | Drug Info | [35] | |||
| 11 | 3-(1H-Indol-2-yl)-1H-quinolin-2-one | Drug Info | [36] | |||
| 12 | 4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole | Drug Info | [37] | |||
| 13 | 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol | Drug Info | [38] | |||
| 14 | 6-(3-aminopropyl)benzo[h]isoquinolin-1(2H)-one | Drug Info | [39] | |||
| 15 | 6-MORPHOLIN-4-YL-9H-PURINE | Drug Info | [35] | |||
| 16 | 9-chlorobenzo[h]isoquinolin-1(2H)-one | Drug Info | [39] | |||
| 17 | 9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione | Drug Info | [40] | |||
| 18 | A-432411 | Drug Info | [41] | |||
| 19 | ARRY-575 | Drug Info | [42] | |||
| 20 | BIS-IMIDE A | Drug Info | [43] | |||
| 21 | Bisindolylmaleimide-I | Drug Info | [44] | |||
| 22 | BX-795 | Drug Info | [45] | |||
| 23 | BX-912 | Drug Info | [45] | |||
| 24 | CCT244747 | Drug Info | [46] | |||
| 25 | Chk1-A | Drug Info | [42] | |||
| 26 | CI-1040 | Drug Info | [44] | |||
| 27 | DEBROMOHYMENIALDISINE | Drug Info | [47] | |||
| 28 | GRANULATIMIDE | Drug Info | [43] | |||
| 29 | Isogranulatimide | Drug Info | [43] | |||
| 30 | KN-62 | Drug Info | [44] | |||
| 31 | N-(5,6-DIPHENYLFURO[2,3-D]PYRIMIDIN-4-YL)GLYCINE | Drug Info | [35] | |||
| 32 | NU-6102 | Drug Info | [48] | |||
| 33 | PMID17935989C25 | Drug Info | [49] | |||
| 34 | PMID19364658C33 | Drug Info | [50] | |||
| 35 | PMID20855207C25 | Drug Info | [51] | |||
| 36 | RO-316233 | Drug Info | [44] | |||
| 37 | S-024 | Drug Info | [42] | |||
| 38 | S-070 | Drug Info | [42] | |||
| 39 | SB 218078 | Drug Info | [52] | |||
| 40 | SB218078 | Drug Info | [53] | |||
| 41 | V158411 | Drug Info | [54] | |||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
|---|---|---|---|---|---|---|
| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
|---|---|---|---|---|---|---|
| REF 1 | Characterization of an inhibitory dynamic pharmacophore for the ERCC1-XPA interaction using a combined molecular dynamics and virtual screening app... J Mol Graph Model. 2009 Sep;28(2):113-30. | |||||
| REF 2 | URL: 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 3 | ClinicalTrials.gov (NCT00988858) A Study of Advanced or Metastatic Non-small Cell Lung Cancer. U.S. National Institutes of Health. | |||||
| REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 5 | URL: 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 6 | 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 7 | ClinicalTrials.gov (NCT00082017) UCN-01 (7-Hydroxystaurosporine) to Treat Relapsed T-Cell Lymphomas. U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT02632448) A Study of LY2880070 in Participants With Advanced or Metastatic Cancer. U.S. National Institutes of Health. | |||||
| REF 9 | URL: 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 10 | 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 11 | 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 12 | ClinicalTrials.gov (NCT00779584) A Dose-escalation Study of MK-8776 (SCH 900776) With and Without Gemcitabine in Participants With Solid Tumors or Lymphoma (MK-8776-002/P05248). U.S. National Institutes of Health. | |||||
| REF 13 | 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 14 | URL: 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 15 | 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 16 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034639) | |||||
| REF 17 | ClinicalTrials.gov (NCT00234481) Safety Study of XL844 in Subjects With Chronic Lymphocytic Leukemia. U.S. National Institutes of Health. | |||||
| REF 18 | Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs. 2014 Apr;32(2):213-26. | |||||
| REF 19 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 20 | 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 21 | CHK1 inhibition as a strategy for targeting Fanconi Anemia (FA) DNA repair pathway deficient tumors. Mol Cancer. 2009 Apr 16;8:24. | |||||
| REF 22 | 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 23 | The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem. 2009 Jun;9(5):550-9. | |||||
| REF 24 | Cyclin-dependent kinase inhibitors as potential targeted anticancer agents. Invest New Drugs. 2009 Dec;27(6):586-94. | |||||
| REF 25 | A phase Ib study of oral Chk1 inhibitor LY2880070 in combination with gemcitabine in patients with advanced or metastatic cancer. Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 3581-3581. | |||||
| REF 26 | Clinical pipeline report, company report or official report of AstraZeneca (2009). | |||||
| REF 27 | Quantitative assessment of BCL-2:BIM complexes as a pharmacodynamic marker for venetoclax (ABT-199). | |||||
| REF 28 | Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells. Int J Mol Sci. 2019 Aug 22;20(17):4095. | |||||
| REF 29 | National Cancer Institute Drug Dictionary (drug id 730054). | |||||
| REF 30 | 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 31 | Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70. | |||||
| REF 32 | Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. | |||||
| REF 33 | National Cancer Institute Drug Dictionary (drug id 701310). | |||||
| REF 34 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
| REF 35 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 36 | Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors. Bioorg Med Chem Lett. 2006 Nov 15;16(22):5907-12. | |||||
| REF 37 | Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47. | |||||
| REF 38 | 4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006 Nov 2;49(22):6500-9. | |||||
| REF 39 | Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase. Bioorg Med Chem Lett. 2007 Nov 15;17(22):6280-5. | |||||
| REF 40 | 4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione inhibitors of the checkpoint kinase Wee1. Structure-activity relationships for chromophore modific... J Med Chem. 2006 Aug 10;49(16):4896-911. | |||||
| REF 41 | Synthesis of selenophene derivatives as novel CHK1 inhibitors. Bioorg Med Chem Lett. 2010 Sep 1;20(17):5065-8. | |||||
| REF 42 | URL: 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 43 | 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... Eur J Med Chem. 2008 Feb;43(2):282-92. | |||||
| REF 44 | Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105. | |||||
| REF 45 | Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2005 May 20;280(20):19867-74. | |||||
| REF 46 | 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 47 | Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4319-21. | |||||
| REF 48 | Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: protein structure-guided design and SAR. Bioorg Med Chem Lett. 2006 Mar 1;16(5):1353-7. | |||||
| REF 49 | Macrocyclic ureas as potent and selective Chk1 inhibitors: an improved synthesis, kinome profiling, structure-activity relationships, and prelimina... Bioorg Med Chem Lett. 2007 Dec 1;17(23):6593-601. | |||||
| REF 50 | 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 51 | 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 52 | 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 53 | Chk1 inhibitor synergizes quinacrine mediated apoptosis in breast cancer cells by compromising the base excision repair cascade. Biochem Pharmacol. 2016 Apr 1;105:23-33. | |||||
| REF 54 | Cell Density Affects the Detection of Chk1 Target Engagement by the Selective Inhibitor V158411. SLAS Discov. 2018 Feb;23(2):144-153. | |||||
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