Target Information
Target General Infomation | |||||
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Target ID |
T56418
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Former ID |
TTDI02271
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Target Name |
ALK tyrosine kinase receptor
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Gene Name |
ALK
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Synonyms |
Anaplastic lymphoma kinase; CD246; ALK
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Target Type |
Successful
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Disease | Advanced solid tumor [ICD9: 140-199; ICD10: C00-C75, C7A, C7B] | ||||
ALK-positive advanced or metastatic NSCLC [ICD9: 162; ICD10: C33, C34] | |||||
Cancer [ICD9: 140-229; ICD10: C00-C96] | |||||
Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86] | |||||
Late-stage B-cell lymphoma [ICD9: 140-199, 202.8, 210-229; ICD10: C00-C75, C7A, C7B, C81-C86, C85.1, D10-D36, D3A] | |||||
Non-small cell lung cancer [ICD10: C33-C34] | |||||
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48] | |||||
Function |
Neuronal orphan 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. Transduces signals from ligands at the cell surface, through specific 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. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. 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.
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BioChemical Class |
Kinase
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UniProt ID | |||||
EC Number |
EC 2.7.10.1
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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 |
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Structure |
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
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Drugs and Mode of Action | |||||
Drug(s) | Crizotinib | Drug Info | Approved | ALK-positive advanced or metastatic NSCLC | [468091], [531783] |
LDK378 | Drug Info | Approved | Non-small cell lung cancer | [533123], [542418], [551871] | |
AF-802 | Drug Info | Phase 2 | Non-small cell lung cancer | [524315], [542705] | |
AP26113 | Drug Info | Phase 2 | Cancer | [524689], [542707] | |
PF-06463922 | Drug Info | Phase 1/2 | Cancer | [524494], [542499] | |
RXDX 101 | Drug Info | Phase 1/2 | Solid tumours | [532994] | |
TSR-011 | Drug Info | Phase 1/2 | Non-small cell lung cancer | [524619] | |
X-396 | Drug Info | Phase 1/2 | Advanced solid tumor | [523953] | |
ASP3026 | Drug Info | Phase 1 | Late-stage B-cell lymphoma | [523558], [542706] | |
Inhibitor | AF-802 | Drug Info | [531479] | ||
AZD3463 | Drug Info | [543509] | |||
CEP-18050 | Drug Info | [543509] | |||
CEP-28122 | Drug Info | [543509] | |||
compound 15 | Drug Info | [532801] | |||
compound 25b | Drug Info | [531897] | |||
compound 5g | Drug Info | [530930] | |||
compound 5m | Drug Info | [530930] | |||
compound 5n | Drug Info | [530930] | |||
compound 8e | Drug Info | [532627] | |||
CRL-37212 | Drug Info | [543509] | |||
GSK-1838705A | Drug Info | [530446] | |||
NMS-E628 | Drug Info | [543509] | |||
PF-06463922 | Drug Info | [533279] | |||
RXDX 101 | Drug Info | [532994] | |||
TSR-011 | Drug Info | [532061], [550510] | |||
X-396 | Drug Info | [551778] | |||
Modulator | AP26113 | Drug Info | [1572591] | ||
ASP3026 | Drug Info | [542706] | |||
Crizotinib | Drug Info | [551871] | |||
LDK378 | Drug Info | [542418] | |||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
Pathways | |||||
KEGG Pathway | Non-small cell lung cancer | ||||
WikiPathways | Differentiation Pathway | ||||
References | |||||
Ref 468091 | (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. (Ligand id: 4903). | ||||
Ref 523558 | ClinicalTrials.gov (NCT01401504) Study of an Investigational Drug, ASP3026, in Patients With Solid Tumors. U.S. National Institutes of Health. | ||||
Ref 523953 | ClinicalTrials.gov (NCT01625234) Phase 1/2 Study of X-396, an Oral ALK Inhibitor, in Patients With ALK-positive Non-Small Cell Lung Cancer. U.S. National Institutes of Health. | ||||
Ref 524315 | ClinicalTrials.gov (NCT01871805) A Study of CH5424802/RO5424802 in Patients With ALK-Rearranged Non-Small Cell Lung Cancer. U.S. National Institutes of Health. | ||||
Ref 524494 | ClinicalTrials.gov (NCT01970865) A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations. U.S. National Institutes of Health. | ||||
Ref 524619 | ClinicalTrials.gov (NCT02048488) A Phase I/IIa Open-Label, Dose Escalation and Cohort Expansion Trial of Oral TSR-011 in Patients With Advanced Solid Tumors and Lymphomas. U.S. National Institutes ofHealth. | ||||
Ref 524689 | ClinicalTrials.gov (NCT02094573) A Phase 2, Multicenter, Randomized Study of AP26113. U.S. National Institutes of Health. | ||||
Ref 532994 | ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39. | ||||
Ref 542418 | (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. (Ligand id: 7397). | ||||
Ref 542499 | (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. (Ligand id: 7476). | ||||
Ref 542705 | (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. (Ligand id: 7739). | ||||
Ref 542706 | (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. (Ligand id: 7740). | ||||
Ref 530446 | GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. Mol Cancer Ther. 2009 Oct;8(10):2811-20. | ||||
Ref 530930 | Synthesis and structure-activity relationships of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase. Bioorg Med Chem. 2010 Jun 15;18(12):4351-62. | ||||
Ref 531479 | CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011 May 17;19(5):679-90. | ||||
Ref 531897 | Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase. J Med Chem. 2012 May 24;55(10):4580-93. | ||||
Ref 532061 | Treatment of ALK-positive non-small cell lung cancer. Arch Pathol Lab Med. 2012 Oct;136(10):1201-4. | ||||
Ref 532627 | Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J Med Chem.> 2014 Feb 27;57(4):1170-87. | ||||
Ref 532801 | Discovery of a potent inhibitor of anaplastic lymphoma kinase with in vivo antitumor activity. ACS Med Chem Lett. 2010 Sep 1;1(9):493-8. | ||||
Ref 532994 | ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39. | ||||
Ref 533279 | PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models. Cancer Cell. 2015 Jul 13;28(1):70-81. | ||||
Ref 542418 | (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. (Ligand id: 7397). | ||||
Ref 542706 | (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. (Ligand id: 7740). | ||||
Ref 543509 | (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: 1839). |
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