Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTTU902)

• DTT Name: Checkpoint kinase-1 (CHK1)
• Synonyms: Serine/threonine-protein kinase Chk1; Chk1; Cell cycle checkpoint kinase; CHK1 checkpoint homolog
• Gene Name: CHEK1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: CHK1_HUMAN
• TTD ID: T62449
• EC Number: EC 2.7.11.1
• Sequence:
  MAVPFVEDWDLVQTLGEGAYGEVQLAVNRVTEEAVAVKIVDMKRAVDCPENIKKEICINK
  MLNHENVVKFYGHRREGNIQYLFLEYCSGGELFDRIEPDIGMPEPDAQRFFHQLMAGVVY
  LHGIGITHRDIKPENLLLDERDNLKISDFGLATVFRYNNRERLLNKMCGTLPYVAPELLK
  RREFHAEPVDVWSCGIVLTAMLAGELPWDQPSDSCQEYSDWKEKKTYLNPWKKIDSAPLA
  LLHKILVENPSARITIPDIKKDRWYNKPLKKGAKRPRVTSGGVSESPSGFSKHIQSNLDF
  SPVNSASSEENVKYSSSQPEPRTGLSLWDTSPSYIDKLVQGISFSQPTCPDHMLLNSQLL
  GTPGSSQNPWQRLVKRMTRFFTKLDADKSYQCLKETCEKLGYQWKKSCMNQVTISTTDRR
  NNKLIFKVNLLEMDDKILVDFRLSKGDGLEFKRHFLKIKGKLIDIVSSQKIWLPAT
• 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.
• KEGG Pathway:
  Cell cycle (hsa04110)
  p53 signaling pathway (hsa04115)
  HTLV-I infection (hsa05166)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Ubiquitin Mediated Degradation of Phosphorylated Cdc25A (R-HSA-69601)
  Chk1/Chk2(Cds1) mediated inactivation of Cyclin B (R-HSA-75035)
  Activation of ATR in response to replication stress (R-HSA-176187)

Molecular Interaction Atlas (MIA) of This DTT

9 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LY2603618	DMCXRZF	Pancreatic cancer	2C10	Phase 2	[2]
LY2606368	DM4XMF7	Ovarian cancer	2C73	Phase 2	[3]
SCH-900776	DM67EMK	Solid tumour/cancer	2A00-2F9Z	Phase 2	[4]
UCN-01	DMUNJZB	Non-small-cell lung cancer	2C25.Y	Phase 2	[1]
LY2880070	DMADEHZ	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[5]
AZD7762	DM1FW0C	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
GDC-0425	DMDZ26X	Lymphoma	2A80-2A86	Phase 1	[7]
MK-8776	DMAS1RB	Hodgkin lymphoma	2B30	Phase 1	[8]
RG7741	DMK6P9J	Lymphoma	2A80-2A86	Phase 1	[9]

1 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Diamidothiazole derivative 1	DM02V5Q	N. A.	N. A.	Patented	[10]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PF-477736	DMDOTW0	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[11]
RG7602	DMXJAFC	Lymphoma	2A80-2A86	Discontinued in Phase 1	[12]
XL844	DMHTG38	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[13]

33 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(1H-indazol-3-yl)-1H-benzo[d]imidazole	DM0CSH8	Discovery agent	N.A.	Investigative	[14]
2-(cyclohexylamino)benzoic acid	DMPT0MB	Discovery agent	N.A.	Investigative	[14]
3-(1H-Indol-2-yl)-1H-quinolin-2-one	DMS3JCN	Discovery agent	N.A.	Investigative	[15]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[16]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[17]
6-(3-aminopropyl)benzo[h]isoquinolin-1(2H)-one	DMYA4D2	Discovery agent	N.A.	Investigative	[18]
6-MORPHOLIN-4-YL-9H-PURINE	DMTNZKU	Discovery agent	N.A.	Investigative	[14]
9-chlorobenzo[h]isoquinolin-1(2H)-one	DM6EFN2	Discovery agent	N.A.	Investigative	[18]
9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione	DMGCX7E	Discovery agent	N.A.	Investigative	[19]
A-432411	DMQHKIA	Discovery agent	N.A.	Investigative	[20]
ARRY-575	DMIRTF5	Solid tumour/cancer	2A00-2F9Z	Investigative	[21]
BIS-IMIDE A	DM0MK6D	Discovery agent	N.A.	Investigative	[22]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[23]
BX-795	DMRIMLJ	Discovery agent	N.A.	Investigative	[24]
BX-912	DMZA45C	Discovery agent	N.A.	Investigative	[24]
CCT244747	DMSDH3A	Discovery agent	N.A.	Investigative	[25]
Chk1-A	DMLCZ3D	Solid tumour/cancer	2A00-2F9Z	Investigative	[21]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[23]
DEBROMOHYMENIALDISINE	DMDLER8	Discovery agent	N.A.	Investigative	[26]
GRANULATIMIDE	DM65SQK	Discovery agent	N.A.	Investigative	[22]
Isogranulatimide	DMI6NJ1	Discovery agent	N.A.	Investigative	[22]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[23]
N-(5,6-DIPHENYLFURO[2,3-D]PYRIMIDIN-4-YL)GLYCINE	DMEW3L0	Discovery agent	N.A.	Investigative	[14]
NU-6102	DMMOFKD	Discovery agent	N.A.	Investigative	[27]
PMID17935989C25	DML8ZBR	Discovery agent	N.A.	Investigative	[28]
PMID19364658C33	DMSE1C3	Discovery agent	N.A.	Investigative	[29]
PMID20855207C25	DMNEB6J	Discovery agent	N.A.	Investigative	[30]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[23]
S-024	DMT36AB	Solid tumour/cancer	2A00-2F9Z	Investigative	[21]
S-070	DMANSCK	Solid tumour/cancer	2A00-2F9Z	Investigative	[21]
SB 218078	DMN1G5S	Discovery agent	N.A.	Investigative	[31]
SB218078	DM7LARD	Triple negative breast cancer	2C60-2C65	Investigative	[32]
V158411	DMXLHIO	Triple negative breast cancer	2C60-2C65	Investigative	[33]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	7.22E-191	1.43	4.74

References

• [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.
• [2] Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs. 2014 Apr;32(2):213-26.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] 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.
• [5] 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.
• [6] Clinical pipeline report, company report or official report of AstraZeneca (2009).
• [7] Quantitative assessment of BCL-2:BIM complexes as a pharmacodynamic marker for venetoclax (ABT-199).
• [8] 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.
• [9] National Cancer Institute Drug Dictionary (drug id 730054).
• [10] Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.
• [11] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [12] National Cancer Institute Drug Dictionary (drug id 701310).
• [13] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [14] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [15] Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors. Bioorg Med Chem Lett. 2006 Nov 15;16(22):5907-12.
• [16] Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47.
• [17] 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.
• [18] Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase. Bioorg Med Chem Lett. 2007 Nov 15;17(22):6280-5.
• [19] 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.
• [20] Synthesis of selenophene derivatives as novel CHK1 inhibitors. Bioorg Med Chem Lett. 2010 Sep 1;20(17):5065-8.
• [21] 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).
• [22] 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.
• [23] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [24] Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2005 May 20;280(20):19867-74.
• [25] 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.
• [26] Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4319-21.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6739-43.
• [31] 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.
• [32] 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.
• [33] Cell Density Affects the Detection of Chk1 Target Engagement by the Selective Inhibitor V158411. SLAS Discov. 2018 Feb;23(2):144-153.