Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV3P4V8)

• DOT Name: ALK tyrosine kinase receptor (ALK)
• Synonyms: EC 2.7.10.1; Anaplastic lymphoma kinase; CD antigen CD246
• Gene Name: ALK
• Related Disease: Neuroblastoma, susceptibility to, 3
• UniProt ID: ALK_HUMAN
• PDB ID: 2KUP ; 2KUQ ; 2XB7 ; 2XBA ; 2XP2 ; 2YFX ; 2YHV ; 2YJR ; 2YJS ; 2YS5 ; 2YT2 ; 3AOX ; 3L9P ; 3LCS ; 3LCT ; 4ANL ; 4ANQ ; 4ANS ; 4CCB ; 4CCU ; 4CD0 ; 4CLI ; 4CLJ ; 4CMO ; 4CMT ; 4CMU ; 4CNH ; 4CTB ; 4CTC ; 4DCE ; 4FNW ; 4FNX ; 4FNY ; 4FNZ ; 4FOB ; 4FOC ; 4FOD ; 4JOA ; 4MKC ; 4TT7 ; 4Z55 ; 5A9U ; 5AA8 ; 5AA9 ; 5AAA ; 5AAB ; 5AAC ; 5FTO ; 5FTQ ; 5IMX ; 5IUG ; 5IUH ; 5IUI ; 5KZ0 ; 5VZ5 ; 6AT9 ; 6CDT ; 6E0R ; 6EBW ; 6EDL ; 6MX8 ; 7BTT ; 7JY4 ; 7JYR ; 7JYS ; 7JYT ; 7LRZ ; 7LS0 ; 7MZW ; 7MZY ; 7N00 ; 7NWZ ; 7NX3 ; 7NX4 ; 7R7K ; 7R7R ; 8ARJ
• EC Number: 2.7.10.1
• Pfam ID: PF12810 ; PF00629 ; PF07714
• Sequence:
  MGAIGLLWLLPLLLSTAAVGSGMGTGQRAGSPAAGPPLQPREPLSYSRLQRKSLAVDFVV
  PSLFRVYARDLLLPPSSSELKAGRPEARGSLALDCAPLLRLLGPAPGVSWTAGSPAPAEA
  RTLSRVLKGGSVRKLRRAKQLVLELGEEAILEGCVGPPGEAAVGLLQFNLSELFSWWIRQ
  GEGRLRIRLMPEKKASEVGREGRLSAAIRASQPRLLFQIFGTGHSSLESPTNMPSPSPDY
  FTWNLTWIMKDSFPFLSHRSRYGLECSFDFPCELEYSPPLHDLRNQSWSWRRIPSEEASQ
  MDLLDGPGAERSKEMPRGSFLLLNTSADSKHTILSPWMRSSSEHCTLAVSVHRHLQPSGR
  YIAQLLPHNEAAREILLMPTPGKHGWTVLQGRIGRPDNPFRVALEYISSGNRSLSAVDFF
  ALKNCSEGTSPGSKMALQSSFTCWNGTVLQLGQACDFHQDCAQGEDESQMCRKLPVGFYC
  NFEDGFCGWTQGTLSPHTPQWQVRTLKDARFQDHQDHALLLSTTDVPASESATVTSATFP
  APIKSSPCELRMSWLIRGVLRGNVSLVLVENKTGKEQGRMVWHVAAYEGLSLWQWMVLPL
  LDVSDRFWLQMVAWWGQGSRAIVAFDNISISLDCYLTISGEDKILQNTAPKSRNLFERNP
  NKELKPGENSPRQTPIFDPTVHWLFTTCGASGPHGPTQAQCNNAYQNSNLSVEVGSEGPL
  KGIQIWKVPATDTYSISGYGAAGGKGGKNTMMRSHGVSVLGIFNLEKDDMLYILVGQQGE
  DACPSTNQLIQKVCIGENNVIEEEIRVNRSVHEWAGGGGGGGGATYVFKMKDGVPVPLII
  AAGGGGRAYGAKTDTFHPERLENNSSVLGLNGNSGAAGGGGGWNDNTSLLWAGKSLQEGA
  TGGHSCPQAMKKWGWETRGGFGGGGGGCSSGGGGGGYIGGNAASNNDPEMDGEDGVSFIS
  PLGILYTPALKVMEGHGEVNIKHYLNCSHCEVDECHMDPESHKVICFCDHGTVLAEDGVS
  CIVSPTPEPHLPLSLILSVVTSALVAALVLAFSGIMIVYRRKHQELQAMQMELQSPEYKL
  SKLRTSTIMTDYNPNYCFAGKTSSISDLKEVPRKNITLIRGLGHGAFGEVYEGQVSGMPN
  DPSPLQVAVKTLPEVCSEQDELDFLMEALIISKFNHQNIVRCIGVSLQSLPRFILLELMA
  GGDLKSFLRETRPRPSQPSSLAMLDLLHVARDIACGCQYLEENHFIHRDIAARNCLLTCP
  GPGRVAKIGDFGMARDIYRASYYRKGGCAMLPVKWMPPEAFMEGIFTSKTDTWSFGVLLW
  EIFSLGYMPYPSKSNQEVLEFVTSGGRMDPPKNCPGPVYRIMTQCWQHQPEDRPNFAIIL
  ERIEYCTQDPDVINTALPIEYGPLVEEEEKVPVRPKDPEGVPPLLVSQQAKREEERSPAA
  PPPLPTTSSGKAAKKPTAAEISVRVPRGPAVEGGHVNMAFSQSNPPSELHKVHGSRNKPT
  SLWNPTYGSWFTEKPTKKNNPIAKKEPHDRGNLGLEGSCTVPPNVATGRLPGASLLLEPS
  SLTANMKEVPLFRLRHFPCGNVNYGYQQQGLPLEAATAPGAGHYEDTILKSKNSMNQPGP
• Function: Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Also acts as a key thinness protein involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis. Following activation by ALKAL2 ligand at the cell surface, transduces an extracellular signal into an intracellular response. In contrast, ALKAL1 is not a potent physiological ligand for ALK. Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK). PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK.
• Tissue Specificity: Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells.
• KEGG Pathway:
  Pathways in cancer (hsa05200)
  Non-small cell lung cancer (hsa05223)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway:
  ALK mutants bind TKIs (R-HSA-9700645)
  ASP-3026-resistant ALK mutants (R-HSA-9717264)
  NVP-TAE684-resistant ALK mutants (R-HSA-9717301)
  alectinib-resistant ALK mutants (R-HSA-9717316)
  brigatinib-resistant ALK mutants (R-HSA-9717319)
  ceritinib-resistant ALK mutants (R-HSA-9717323)
  crizotinib-resistant ALK mutants (R-HSA-9717326)
  lorlatinib-resistant ALK mutants (R-HSA-9717329)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  Nuclear events stimulated by ALK signaling in cancer (R-HSA-9725371)
  Signaling by ALK (R-HSA-201556)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma, susceptibility to, 3	DIS3074Y	Definitive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Marinol	DM70IK5	Approved	ALK tyrosine kinase receptor (ALK) decreases the response to substance of Marinol.	[11]
Adenosine triphosphate	DM79F6G	Approved	ALK tyrosine kinase receptor (ALK) affects the binding of Adenosine triphosphate.	[12]
Crizotinib	DM4F29C	Approved	ALK tyrosine kinase receptor (ALK) decreases the response to substance of Crizotinib.	[13]
Pemetrexed	DMMX2E6	Approved	ALK tyrosine kinase receptor (ALK) affects the response to substance of Pemetrexed.	[14]
NVP-TAE684	DMFZXI2	Investigative	ALK tyrosine kinase receptor (ALK) decreases the response to substance of NVP-TAE684.	[15]
Torin2	DMC6U93	Investigative	ALK tyrosine kinase receptor (ALK) decreases the response to substance of Torin2.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ALK tyrosine kinase receptor (ALK).	[2]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of ALK tyrosine kinase receptor (ALK).	[5]
Masoprocol	DMMVNZ0	Approved	Masoprocol decreases the activity of ALK tyrosine kinase receptor (ALK).	[4]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of ALK tyrosine kinase receptor (ALK).	[7]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the activity of ALK tyrosine kinase receptor (ALK).	[8]
BW A4C	DMNUMDG	Terminated	BW A4C decreases the activity of ALK tyrosine kinase receptor (ALK).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of ALK tyrosine kinase receptor (ALK).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the phosphorylation of ALK tyrosine kinase receptor (ALK).	[4]
Ceritinib	DMB920Z	Approved	Ceritinib decreases the phosphorylation of ALK tyrosine kinase receptor (ALK).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ALK tyrosine kinase receptor (ALK).	[9]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID26882240-Compound-32	DMJS4RP	Patented	PMID26882240-Compound-32 decreases the stability of ALK tyrosine kinase receptor (ALK).	[10]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] All-trans retinoic acid downregulates ALK in neuroblastoma cell lines and induces apoptosis in neuroblastoma cell lines with activated ALK. Cancer Lett. 2010 Nov 28;297(2):220-5. doi: 10.1016/j.canlet.2010.05.014. Epub 2010 Jun 23.
• [3] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [4] Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas. Oncogene. 2009 Jul 23;28(29):2690-6.
• [5] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [6] 1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-(dimethylamino)ethyl)imidazolidin-2-one (ZX-42) inhibits cell proliferation and induces apoptosis via inhibiting ALK and its downstream pathways in Karpas299 cells. Toxicol Appl Pharmacol. 2022 Sep 1;450:116156. doi: 10.1016/j.taap.2022.116156. Epub 2022 Jul 6.
• [7] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [8] The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res. 2010 Dec 15;70(24):10038-43. doi: 10.1158/0008-5472.CAN-10-2956. Epub 2010 Oct 28.
• [9] 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.
• [10] Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants. Clin Cancer Res. 2012 Sep 1;18(17):4682-90. doi: 10.1158/1078-0432.CCR-11-3260. Epub 2012 Aug 21.
• [11] Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action. Cell Death Differ. 2011 Jun;18(6):959-73. doi: 10.1038/cdd.2010.170. Epub 2011 Jan 14.
• [12] Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci Transl Med. 2011 Nov 9;3(108):108ra114. doi: 10.1126/scitranslmed.3002950.
• [13] Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012 Feb 8;4(120):120ra17. doi: 10.1126/scitranslmed.3003316. Epub 2012 Jan 25.
• [14] Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol. 2011 Apr;6(4):774-80. doi: 10.1097/JTO.0b013e31820cf053.
• [15] A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res. 2011 Sep 15;71(18):6051-60. doi: 10.1158/0008-5472.CAN-11-1340. Epub 2011 Jul 26.
• [16] The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell. 2012 Jul 10;22(1):117-30. doi: 10.1016/j.ccr.2012.06.001.