Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVVM637)

• DOT Name: Inactive tyrosine-protein kinase PEAK1 (PEAK1)
• Synonyms: Pseudopodium-enriched atypical kinase 1; Sugen kinase 269; Tyrosine-protein kinase SgK269
• Gene Name: PEAK1
• Related Disease:
  Parkinson disease
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Neoplasm
  Pancreatic cancer
  Metastatic malignant neoplasm
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Lung cancer
  Lung carcinoma
  Matthew-Wood syndrome
  Pancreatic ductal carcinoma
  Rectal carcinoma
• UniProt ID: PEAK1_HUMAN
• PDB ID: 6BHC; 8DGM
• Pfam ID: PF00069
• Sequence:
  MSACNTFTEHVWKPGECKNCFKPKSLHQLPPDPEKAPITHGNVKTNANHSNNHRIRNTGN
  FRPPVAKKPTIAVKPTMIVADGQSICGELSIQEHCENKPVIIGWNRNRAALSQKPLNNNN
  EDDEGISHVPKPYGNNDSAKKMSDNNNGLTEVLKEIAGLDTAPQIRGNETNSRETFLGRI
  NDCYKRSLERKLPPSCMIGGIKETQGKHVILSGSTEVISNEGGRFCYPEFSSGEESEEDV
  LFSNMEEEHESWDESDEELLAMEIRMRGQPRFANFRANTLSPVRFFVDKKWNTIPLRNKS
  LQRICAVDYDDSYDEILNGYEENSVVSYGQGSIQSMVSSDSTSPDSSLTEESRSETASSL
  SQKICNGGLSPGNPGDSKDMKEIEPNYESPSSNNQDKDSSQASKSSIKVPETHKAVLALR
  LEEKDGKIAVQTEKEESKASTDVAGQAVTINLVPTEEQAKPYRVVNLEQPLCKPYTVVDV
  SAAMASEHLEGPVNSPKTKSSSSTPNSPVTSSSLTPGQISAHFQKSSAIRYQEVWTSSTS
  PRQKIPKVELITSGTGPNVPPRKNCHKSAPTSPTATNISSKTIPVKSPNLSEIKFNSYNN
  AGMPPFPIIIHDEPTYARSSKNAIKVPIVINPNAYDNLAIYKSFLGTSGELSVKEKTTSV
  ISHTYEEIETESKVPDNTTSKTTDCLQTKGFSNSTEHKRGSVAQKVQEFNNCLNRGQSSP
  QRSYSSSHSSPAKIQRATQEPVAKIEGTQESQMVGSSSTREKASTVLSQIVASIQPPQSP
  PETPQSGPKACSVEELYAIPPDADVAKSTPKSTPVRPKSLFTSQPSGEAEAPQTTDSPTT
  KVQKDPSIKPVTPSPSKLVTSPQSEPPAPFPPPRSTSSPYHAGNLLQRHFTNWTKPTSPT
  RSTEAESVLHSEGSRRAADAKPKRWISFKSFFRRRKTDEEDDKEKEREKGKLVGLDGTVI
  HMLPPPPVQRHHWFTEAKGESSEKPAIVFMYRCDPAQGQLSVDQSKARTDQAAVMEKGRA
  ENALLQDSEKKRSHSSPSQIPKKILSHMTHEVTEDFSPRDPRTVVGKQDGRGCTSVTTAL
  SLPELEREDGKEDISDPMDPNPCSATYSNLGQSRAAMIPPKQPRQPKGAVDDAIAFGGKT
  DQEAPNASQPTPPPLPKKMIIRANTEPISKDLQKSMESSLCVMANPTYDIDPNWDASSAG
  SSISYELKGLDIESYDSLERPLRKERPVPSAANSISSLTTLSIKDRFSNSMESLSSRRGP
  SCRQGRGIQKPQRQALYRGLENREEVVGKIRSLHTDALKKLAVKCEDLFMAGQKDQLRFG
  VDSWSDFRLTSDKPCCEAGDAVYYTASYAKDPLNNYAVKICKSKAKESQQYYHSLAVRQS
  LAVHFNIQQDCGHFLAEVPNRLLPWEDPDDPEKDEDDMEETEEDAKGETDGKNPKPCSEA
  ASSQKENQGVMSKKQRSHVVVITREVPCLTVADFVRDSLAQHGKSPDLYERQVCLLLLQL
  CSGLEHLKPYHVTHCDLRLENLLLVHYQPGGTAQGFGPAEPSPTSSYPTRLIVSNFSQAK
  QKSHLVDPEILRDQSRLAPEIITATQYKKCDEFQTGILIYEMLHLPNPFDENPELKEREY
  TRADLPRIPFRSPYSRGLQQLASCLLNPNPSERILISDAKGILQCLLWGPREDLFQTFTA
  CPSLVQRNTLLQNWLDIKRTLLMIKFAEKSLDREGGISLEDWLCAQYLAFATTDSLSCIV
  KILQHR
• Function: Probable catalytically inactive kinase. Scaffolding protein that regulates the cytoskeleton to control cell spreading and migration by modulating focal adhesion dynamics. Acts as a scaffold for mediating EGFR signaling.
• Reactome Pathway:
  RHOV GTPase cycle (R-HSA-9013424)
  RHOU GTPase cycle (R-HSA-9013420)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Pancreatic cancer	DISJC981	Strong	Biomarker	[4]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[5]
Colon cancer	DISVC52G	Limited	Altered Expression	[6]
Colon carcinoma	DISJYKUO	Limited	Altered Expression	[6]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[2]
Lung cancer	DISCM4YA	Limited	Altered Expression	[5]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[5]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[4]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[4]
Rectal carcinoma	DIS8FRR7	Limited	Altered Expression	[6]

9 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 Inactive tyrosine-protein kinase PEAK1 (PEAK1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Inactive tyrosine-protein kinase PEAK1 (PEAK1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inactive tyrosine-protein kinase PEAK1 (PEAK1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Inactive tyrosine-protein kinase PEAK1 (PEAK1).	[10]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Inactive tyrosine-protein kinase PEAK1 (PEAK1).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Inactive tyrosine-protein kinase PEAK1 (PEAK1).	[12]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Inactive tyrosine-protein kinase PEAK1 (PEAK1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Inactive tyrosine-protein kinase PEAK1 (PEAK1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Inactive tyrosine-protein kinase PEAK1 (PEAK1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Inactive tyrosine-protein kinase PEAK1 (PEAK1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Inactive tyrosine-protein kinase PEAK1 (PEAK1).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Inactive tyrosine-protein kinase PEAK1 (PEAK1).	[16]

References

• [1] The crystal structure of pseudokinase PEAK1 (Sugen kinase 269) reveals an unusual catalytic cleft and a novel mode of kinase fold dimerization.J Biol Chem. 2018 Feb 2;293(5):1642-1650. doi: 10.1074/jbc.RA117.000751. Epub 2017 Dec 6.
• [2] The PEAK1-PPP1R12B axis inhibits tumor growth and metastasis by regulating Grb2/PI3K/Akt signalling in colorectal cancer.Cancer Lett. 2019 Feb 1;442:383-395. doi: 10.1016/j.canlet.2018.11.014. Epub 2018 Nov 22.
• [3] DHPS-dependent hypusination of eIF5A1/2 is necessary for TGF/fibronectin-induced breast cancer metastasis and associates with prognostically unfavorable genomic alterations in TP53.Biochem Biophys Res Commun. 2019 Nov 19;519(4):838-845. doi: 10.1016/j.bbrc.2019.09.075. Epub 2019 Sep 24.
• [4] eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth.Cancer Res. 2017 Apr 15;77(8):1997-2007. doi: 10.1158/0008-5472.CAN-16-2594. Epub 2017 Apr 5.
• [5] Overexpression of PEAK1 contributes to epithelial-mesenchymal transition and tumor metastasis in lung cancer through modulating ERK1/2 and JAK2 signaling.Cell Death Dis. 2018 Jul 23;9(8):802. doi: 10.1038/s41419-018-0817-1.
• [6] PEAK1, acting as a tumor promoter in colorectal cancer, is regulated by the EGFR/KRas signaling axis and miR-181d.Cell Death Dis. 2018 Feb 15;9(3):271. doi: 10.1038/s41419-018-0320-8.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [11] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.