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
Click to Show/Hide
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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) | [+] 6 Clinical Trial Drugs | + | ||||
| 1 | LY2603618 | Drug Info | Phase 2 | Pancreatic cancer | [3], [4] | |
| 2 | LY2606368 | Drug Info | Phase 2 | Ovarian cancer | [5] | |
| 3 | SCH-900776 | Drug Info | Phase 2 | Solid tumour/cancer | [6], [7] | |
| 4 | AZD7762 | Drug Info | Phase 1 | Solid tumour/cancer | [10], [11] | |
| 5 | GDC-0425 | Drug Info | Phase 1 | Lymphoma | [12] | |
| 6 | RG7741 | Drug Info | Phase 1 | Lymphoma | [13] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | RG7602 | Drug Info | Discontinued in Phase 1 | Lymphoma | [16] | |
| 2 | 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 | [22] | |||
| 3 | RG7741 | Drug Info | [23], [24] | |||
| 4 | RG7602 | Drug Info | [26] | |||
| 5 | XL844 | Drug Info | [27] | |||
| Inhibitor | [+] 30 Inhibitor drugs | + | ||||
| 1 | LY2606368 | Drug Info | [5], [19] | |||
| 2 | SCH-900776 | Drug Info | [20] | |||
| 3 | AZD7762 | Drug Info | [21] | |||
| 4 | Diamidothiazole derivative 1 | Drug Info | [25] | |||
| 5 | 2-(cyclohexylamino)benzoic acid | Drug Info | [28] | |||
| 6 | 3-(1H-Indol-2-yl)-1H-quinolin-2-one | Drug Info | [29] | |||
| 7 | 4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole | Drug Info | [30] | |||
| 8 | 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol | Drug Info | [31] | |||
| 9 | 6-(3-aminopropyl)benzo[h]isoquinolin-1(2H)-one | Drug Info | [32] | |||
| 10 | 6-MORPHOLIN-4-YL-9H-PURINE | Drug Info | [28] | |||
| 11 | 9-chlorobenzo[h]isoquinolin-1(2H)-one | Drug Info | [32] | |||
| 12 | A-432411 | Drug Info | [33] | |||
| 13 | ARRY-575 | Drug Info | [34] | |||
| 14 | BIS-IMIDE A | Drug Info | [35] | |||
| 15 | Bisindolylmaleimide-I | Drug Info | [36] | |||
| 16 | BX-795 | Drug Info | [37] | |||
| 17 | BX-912 | Drug Info | [37] | |||
| 18 | Chk1-A | Drug Info | [34] | |||
| 19 | CI-1040 | Drug Info | [36] | |||
| 20 | DEBROMOHYMENIALDISINE | Drug Info | [38] | |||
| 21 | GRANULATIMIDE | Drug Info | [35] | |||
| 22 | KN-62 | Drug Info | [36] | |||
| 23 | N-(5,6-DIPHENYLFURO[2,3-D]PYRIMIDIN-4-YL)GLYCINE | Drug Info | [28] | |||
| 24 | PMID17935989C25 | Drug Info | [39] | |||
| 25 | PMID19364658C33 | Drug Info | [40] | |||
| 26 | PMID20855207C25 | Drug Info | [41] | |||
| 27 | RO-316233 | Drug Info | [36] | |||
| 28 | S-024 | Drug Info | [34] | |||
| 29 | S-070 | Drug Info | [34] | |||
| 30 | SB 218078 | Drug Info | [42] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Adenine | Ligand Info | |||||
| Structure Description | Crystal structure of CHK1-10pt-mutant complex with adenine | PDB:7BJE | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | Yes | [43] |
| PDB Sequence |
PFVEDWDLVQ
13 TLGEGAYGEV23 QLAVNRVTEE33 AVAVKIVDMN51 IKKEICILKM61 LNHENVIKFY 71 GHRREGNIQY81 LFMELASGGS91 LFDRIEPDIG101 MPEPDAQRFF111 HQLMAGVVYL 121 HGIGITHRDI131 KPHNLLLDER141 DNLKIADYSL151 ATVFRYNNRE161 RLLNKMCGTL 171 PYVAPELLKR181 REFHAEPVDV191 WSCGIVLTAM201 LAGELPWDQP211 SDSCQEYSDW 221 KEKKTYLNPW231 KKIDSAPLAL241 LHKILVENPS251 ARITIPDIKK261 DRWYNKPLK |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: UCN-01 | Ligand Info | |||||
| Structure Description | The Complex Structure Of Checkpoint Kinase Chk1/UCN-01 | PDB:1NVQ | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [44] |
| PDB Sequence |
VPFVEDWDLV
12 QTLGEGAYGE22 VQLAVNRVTE32 EAVAVKIVDM42 KNIKKEICIN59 KMLNHENVVK 69 FYGHRREGNI79 QYLFLEYCSG89 GELFDRIEPD99 IGMPEPDAQR109 FFHQLMAGVV 119 YLHGIGITHR129 DIKPENLLLD139 ERDNLKISDF149 GLATVFRYNN159 RERLLNKMCG 169 TLPYVAPELL179 KRREFHAEPV189 DVWSCGIVLT199 AMLAGELPWD209 QPSDSCQEYS 219 DWKEKKTYLN229 PWKKIDSAPL239 ALLHKILVEN249 PSARITIPDI259 KKDRWYNKPL 269 KKGA
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Cell cycle | hsa04110 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| p53 signaling pathway | hsa04115 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Cellular senescence | hsa04218 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Degree | 63 | Degree centrality | 6.77E-03 | Betweenness centrality | 3.25E-03 |
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| Closeness centrality | 2.53E-01 | Radiality | 1.44E+01 | Clustering coefficient | 2.33E-01 |
| Neighborhood connectivity | 4.41E+01 | Topological coefficient | 5.50E-02 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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 | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| 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 | |||||
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| 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 | ClinicalTrials.gov (NCT00082017) UCN-01 (7-Hydroxystaurosporine) to Treat Relapsed T-Cell Lymphomas. U.S. National Institutes of Health. | |||||
| REF 3 | 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 4 | ClinicalTrials.gov (NCT00988858) A Study of Advanced or Metastatic Non-small Cell Lung Cancer. U.S. National Institutes of Health. | |||||
| REF 5 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 6 | 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 7 | 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 8 | ClinicalTrials.gov (NCT02632448) A Study of LY2880070 in Participants With Advanced or Metastatic Cancer. U.S. National Institutes of Health. | |||||
| REF 9 | 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 10 | 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 11 | 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 12 | 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 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 | Clinical pipeline report, company report or official report of AstraZeneca (2009). | |||||
| REF 22 | Quantitative assessment of BCL-2:BIM complexes as a pharmacodynamic marker for venetoclax (ABT-199). | |||||
| REF 23 | National Cancer Institute Drug Dictionary (drug id 730054). | |||||
| REF 24 | 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 25 | Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70. | |||||
| REF 26 | National Cancer Institute Drug Dictionary (drug id 701310). | |||||
| REF 27 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
| REF 28 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 29 | Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors. Bioorg Med Chem Lett. 2006 Nov 15;16(22):5907-12. | |||||
| REF 30 | Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47. | |||||
| REF 31 | 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 32 | Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase. Bioorg Med Chem Lett. 2007 Nov 15;17(22):6280-5. | |||||
| REF 33 | Synthesis of selenophene derivatives as novel CHK1 inhibitors. Bioorg Med Chem Lett. 2010 Sep 1;20(17):5065-8. | |||||
| REF 34 | 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 35 | 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 36 | Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105. | |||||
| REF 37 | Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2005 May 20;280(20):19867-74. | |||||
| REF 38 | Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4319-21. | |||||
| REF 39 | 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 40 | 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 41 | 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 42 | 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 43 | Design and Synthesis of Pyrrolo[2,3-d]pyrimidine-Derived Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Checkpoint Kinase 1 (CHK1)-Derived Crystallographic Surrogate. J Med Chem. 2021 Jul 22;64(14):10312-10332. | |||||
| REF 44 | Structural basis for Chk1 inhibition by UCN-01. J Biol Chem. 2002 Nov 29;277(48):46609-15. | |||||
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