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]
• Related Disease:
  Lung cancer [ICD-11: 2C25]
  Ovarian cancer [ICD-11: 2C73]
  Pancreatic cancer [ICD-11: 2C10]
  Anal cancer [ICD-11: 2C00]
  Head and neck cancer [ICD-11: 2D42]
  Hodgkin lymphoma [ICD-11: 2B30]
  Lymphoma [ICD-11: 2A80-2A86]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• 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], [4]
SCH-900776	DM67EMK	Solid tumour/cancer	2A00-2F9Z	Phase 2	[5]
UCN-01	DMUNJZB	Non-small-cell lung cancer	2C25.Y	Phase 2	[1], [6], [7], [8], [9]
LY2880070	DMADEHZ	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[10]
AZD7762	DM1FW0C	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
GDC-0425	DMDZ26X	Lymphoma	2A80-2A86	Phase 1	[12]
MK-8776	DMAS1RB	Hodgkin lymphoma	2B30	Phase 1	[13]
RG7741	DMK6P9J	Lymphoma	2A80-2A86	Phase 1	[14], [15]

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	[16]

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	[17]
RG7602	DMXJAFC	Lymphoma	2A80-2A86	Discontinued in Phase 1	[18]
XL844	DMHTG38	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[19]

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	[20]
2-(cyclohexylamino)benzoic acid	DMPT0MB	Discovery agent	N.A.	Investigative	[20]
3-(1H-Indol-2-yl)-1H-quinolin-2-one	DMS3JCN	Discovery agent	N.A.	Investigative	[21]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[22]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[23]
6-(3-aminopropyl)benzo[h]isoquinolin-1(2H)-one	DMYA4D2	Discovery agent	N.A.	Investigative	[24]
6-MORPHOLIN-4-YL-9H-PURINE	DMTNZKU	Discovery agent	N.A.	Investigative	[20]
9-chlorobenzo[h]isoquinolin-1(2H)-one	DM6EFN2	Discovery agent	N.A.	Investigative	[24]
9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione	DMGCX7E	Discovery agent	N.A.	Investigative	[25]
A-432411	DMQHKIA	Discovery agent	N.A.	Investigative	[26]
ARRY-575	DMIRTF5	Solid tumour/cancer	2A00-2F9Z	Investigative	[27]
BIS-IMIDE A	DM0MK6D	Discovery agent	N.A.	Investigative	[28]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[29]
BX-795	DMRIMLJ	Discovery agent	N.A.	Investigative	[30]
BX-912	DMZA45C	Discovery agent	N.A.	Investigative	[30]
CCT244747	DMSDH3A	Discovery agent	N.A.	Investigative	[31]
Chk1-A	DMLCZ3D	Solid tumour/cancer	2A00-2F9Z	Investigative	[27]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[29]
DEBROMOHYMENIALDISINE	DMDLER8	Discovery agent	N.A.	Investigative	[32]
GRANULATIMIDE	DM65SQK	Discovery agent	N.A.	Investigative	[28]
Isogranulatimide	DMI6NJ1	Discovery agent	N.A.	Investigative	[28]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[29]
N-(5,6-DIPHENYLFURO[2,3-D]PYRIMIDIN-4-YL)GLYCINE	DMEW3L0	Discovery agent	N.A.	Investigative	[20]
NU-6102	DMMOFKD	Discovery agent	N.A.	Investigative	[33]
PMID17935989C25	DML8ZBR	Discovery agent	N.A.	Investigative	[34]
PMID19364658C33	DMSE1C3	Discovery agent	N.A.	Investigative	[35]
PMID20855207C25	DMNEB6J	Discovery agent	N.A.	Investigative	[36]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[29]
S-024	DMT36AB	Solid tumour/cancer	2A00-2F9Z	Investigative	[27]
S-070	DMANSCK	Solid tumour/cancer	2A00-2F9Z	Investigative	[27]
SB 218078	DMN1G5S	Discovery agent	N.A.	Investigative	[37]
SB218078	DM7LARD	Triple negative breast cancer	2C60-2C65	Investigative	[38]
V158411	DMXLHIO	Triple negative breast cancer	2C60-2C65	Investigative	[39]

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

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