Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNCNUCO)

• DOT Name: Death-associated protein kinase 1 (DAPK1)
• Synonyms: DAP kinase 1; EC 2.7.11.1
• Gene Name: DAPK1
• Related Disease:
  Follicular lymphoma
  Myelodysplastic syndrome
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  B-cell lymphoma
  Bladder cancer
  Brain cancer
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Cholangiocarcinoma
  Clear cell renal carcinoma
  Conjunctival disorder
  Depression
  Glioblastoma multiforme
  Head-neck squamous cell carcinoma
  Juvenile idiopathic arthritis
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Lymphoma
  Pancreatic cancer
  Papillary renal cell carcinoma
  Prostate cancer
  Small lymphocytic lymphoma
  Stroke
  Tarsal-carpal coalition syndrome
  Urinary bladder cancer
  Urinary bladder neoplasm
  Renal cell carcinoma
  Transitional cell carcinoma
  Autism spectrum disorder
  Colorectal carcinoma
  Nasopharyngeal carcinoma
• UniProt ID: DAPK1_HUMAN
• PDB ID: 1IG1 ; 1JKK ; 1JKL ; 1JKS ; 1JKT ; 1P4F ; 1WVW ; 1WVX ; 1WVY ; 1YR5 ; 2W4J ; 2W4K ; 2X0G ; 2XUU ; 2XZS ; 2Y0A ; 2Y4P ; 2Y4V ; 2YAK ; 3DFC ; 3DGK ; 3EH9 ; 3EHA ; 3F5G ; 3F5U ; 3GU4 ; 3GU5 ; 3GU6 ; 3GU7 ; 3GU8 ; 3GUB ; 3ZXT ; 4B4L ; 4PF4 ; 4TL0 ; 4TXC ; 4UV0 ; 4YO4 ; 4YPD ; 5AUT ; 5AUU ; 5AUV ; 5AUW ; 5AUX ; 5AUY ; 5AUZ ; 5AV0 ; 5AV1 ; 5AV2 ; 5AV3 ; 5AV4 ; 6AAR ; 6FHA ; 6FHB ; 6GY5 ; 6IN4 ; 6QMO ; 6QN4 ; 7CCU ; 7CCV ; 7CCW ; 8IE5 ; 8IE6 ; 8IE7 ; 8IE8
• EC Number: 2.7.11.1
• Pfam ID: PF00023 ; PF12796 ; PF00531 ; PF00069
• Sequence:
  MTVFRQENVDDYYDTGEELGSGQFAVVKKCREKSTGLQYAAKFIKKRRTKSSRRGVSRED
  IEREVSILKEIQHPNVITLHEVYENKTDVILILELVAGGELFDFLAEKESLTEEEATEFL
  KQILNGVYYLHSLQIAHFDLKPENIMLLDRNVPKPRIKIIDFGLAHKIDFGNEFKNIFGT
  PEFVAPEIVNYEPLGLEADMWSIGVITYILLSGASPFLGDTKQETLANVSAVNYEFEDEY
  FSNTSALAKDFIRRLLVKDPKKRMTIQDSLQHPWIKPKDTQQALSRKASAVNMEKFKKFA
  ARKKWKQSVRLISLCQRLSRSFLSRSNMSVARSDDTLDEEDSFVMKAIIHAINDDNVPGL
  QHLLGSLSNYDVNQPNKHGTPPLLIAAGCGNIQILQLLIKRGSRIDVQDKGGSNAVYWAA
  RHGHVDTLKFLSENKCPLDVKDKSGEMALHVAARYGHADVAQLLCSFGSNPNIQDKEEET
  PLHCAAWHGYYSVAKALCEAGCNVNIKNREGETPLLTASARGYHDIVECLAEHGADLNAC
  DKDGHIALHLAVRRCQMEVIKTLLSQGCFVDYQDRHGNTPLHVACKDGNMPIVVALCEAN
  CNLDISNKYGRTPLHLAANNGILDVVRYLCLMGASVEALTTDGKTAEDLARSEQHEHVAG
  LLARLRKDTHRGLFIQQLRPTQNLQPRIKLKLFGHSGSGKTTLVESLKCGLLRSFFRRRR
  PRLSSTNSSRFPPSPLASKPTVSVSINNLYPGCENVSVRSRSMMFEPGLTKGMLEVFVAP
  THHPHCSADDQSTKAIDIQNAYLNGVGDFSVWEFSGNPVYFCCYDYFAANDPTSIHVVVF
  SLEEPYEIQLNQVIFWLSFLKSLVPVEEPIAFGGKLKNPLQVVLVATHADIMNVPRPAGG
  EFGYDKDTSLLKEIRNRFGNDLHISNKLFVLDAGASGSKDMKVLRNHLQEIRSQIVSVCP
  PMTHLCEKIISTLPSWRKLNGPNQLMSLQQFVYDVQDQLNPLASEEDLRRIAQQLHSTGE
  INIMQSETVQDVLLLDPRWLCTNVLGKLLSVETPRALHHYRGRYTVEDIQRLVPDSDVEE
  LLQILDAMDICARDLSSGTMVDVPALIKTDNLHRSWADEEDEVMVYGGVRIVPVEHLTPF
  PCGIFHKVQVNLCRWIHQQSTEGDADIRLWVNGCKLANRGAELLVLLVNHGQGIEVQVRG
  LETEKIKCCLLLDSVCSTIENVMATTLPGLLTVKHYLSPQQLREHHEPVMIYQPRDFFRA
  QTLKETSLTNTMGGYKESFSSIMCFGCHDVYSQASLGMDIHASDLNLLTRRKLSRLLDPP
  DPLGKDWCLLAMNLGLPDLVAKYNTSNGAPKDFLPSPLHALLREWTTYPESTVGTLMSKL
  RELGRRDAADFLLKASSVFKINLDGNGQEAYASSCNSGTSYNSISSVVSR
• Function: Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. Phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. Phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. Phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. Phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. Phosphorylates RPS6, MYL9 and DAPK3. Acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca(2+) influx through NMDA receptor channels, resulting in an irreversible neuronal death. Required together with DAPK3 for phosphorylation of RPL13A upon interferon-gamma activation which is causing RPL13A involvement in transcript-selective translation inhibition.; Isoform 2 cannot induce apoptosis but can induce membrane blebbing.
• Tissue Specificity: Isoform 2 is expressed in normal intestinal tissue as well as in colorectal carcinomas.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Pathways in cancer (hsa05200)
  Bladder cancer (hsa05219)
• Reactome Pathway: Caspase activation via Dependence Receptors in the absence of ligand (R-HSA-418889)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Follicular lymphoma	DISVEUR6	Definitive	Posttranslational Modification	[1]
Myelodysplastic syndrome	DISYHNUI	Definitive	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
B-cell lymphoma	DISIH1YQ	Strong	Posttranslational Modification	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[6]
Brain cancer	DISBKFB7	Strong	Biomarker	[7]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[8]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[8]
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[9]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[9]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[10]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[11]
Conjunctival disorder	DISPTOTB	Strong	Biomarker	[12]
Depression	DIS3XJ69	Strong	Biomarker	[13]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[14]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[15]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[16]
Lung cancer	DISCM4YA	Strong	Biomarker	[17]
Lung carcinoma	DISTR26C	Strong	Biomarker	[17]
Lung neoplasm	DISVARNB	Strong	Biomarker	[18]
Lymphoma	DISN6V4S	Strong	Posttranslational Modification	[19]
Pancreatic cancer	DISJC981	Strong	Biomarker	[20]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[21]
Prostate cancer	DISF190Y	Strong	Biomarker	[22]
Small lymphocytic lymphoma	DIS30POX	Strong	Posttranslational Modification	[23]
Stroke	DISX6UHX	Strong	Biomarker	[5]
Tarsal-carpal coalition syndrome	DISY90L2	Strong	Posttranslational Modification	[24]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	moderate	Altered Expression	[25]
Transitional cell carcinoma	DISWVVDR	moderate	Biomarker	[26]
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[27]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[28]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Posttranslational Modification	[29]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gemcitabine	DMSE3I7	Approved	Death-associated protein kinase 1 (DAPK1) increases the Haematotoxicity ADR of Gemcitabine.	[60]
Mitoxantrone	DMM39BF	Approved	Death-associated protein kinase 1 (DAPK1) affects the response to substance of Mitoxantrone.	[61]

28 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Death-associated protein kinase 1 (DAPK1).	[30]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Death-associated protein kinase 1 (DAPK1).	[31]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Death-associated protein kinase 1 (DAPK1).	[32]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Death-associated protein kinase 1 (DAPK1).	[33]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Death-associated protein kinase 1 (DAPK1).	[34]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Death-associated protein kinase 1 (DAPK1).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Death-associated protein kinase 1 (DAPK1).	[36]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Death-associated protein kinase 1 (DAPK1).	[37]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Death-associated protein kinase 1 (DAPK1).	[38]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Death-associated protein kinase 1 (DAPK1).	[39]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Death-associated protein kinase 1 (DAPK1).	[40]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Death-associated protein kinase 1 (DAPK1).	[41]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Death-associated protein kinase 1 (DAPK1).	[42]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Death-associated protein kinase 1 (DAPK1).	[43]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Death-associated protein kinase 1 (DAPK1).	[43]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Death-associated protein kinase 1 (DAPK1).	[44]
Hydralazine	DMU8JGH	Approved	Hydralazine increases the expression of Death-associated protein kinase 1 (DAPK1).	[46]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Death-associated protein kinase 1 (DAPK1).	[47]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Death-associated protein kinase 1 (DAPK1).	[48]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Death-associated protein kinase 1 (DAPK1).	[49]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Death-associated protein kinase 1 (DAPK1).	[51]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Death-associated protein kinase 1 (DAPK1).	[52]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Death-associated protein kinase 1 (DAPK1).	[53]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Death-associated protein kinase 1 (DAPK1).	[54]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Death-associated protein kinase 1 (DAPK1).	[56]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Death-associated protein kinase 1 (DAPK1).	[57]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Death-associated protein kinase 1 (DAPK1).	[37]
Z-Pro-Prolinal	DM43O2U	Investigative	Z-Pro-Prolinal decreases the expression of Death-associated protein kinase 1 (DAPK1).	[59]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Azacitidine	DMTA5OE	Approved	Azacitidine affects the methylation of Death-associated protein kinase 1 (DAPK1).	[45]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Death-associated protein kinase 1 (DAPK1).	[50]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Death-associated protein kinase 1 (DAPK1).	[55]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the methylation of Death-associated protein kinase 1 (DAPK1).	[58]

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