Target Information

Target General Infomation
Target ID
T56418
Former ID
TTDI02271
Target Name
ALK tyrosine kinase receptor
Gene Name
ALK
Synonyms
Anaplastic lymphoma kinase; CD246; ALK
Target Type
Successful
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]
Late-stage B-cell lymphoma [ICD9: 140-199, 202.8, 210-229; ICD10: C00-C75, C7A, C7B, C81-C86, C85.1, D10-D36, D3A]
Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86]
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.
BioChemical Class
Kinase
UniProt ID
Q9UM73
EC Number
EC 2.7.10.1
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
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
Drugs and Mode of Action
Drug(s) Crizotinib Drug Info Approved ALK-positive advanced or metastatic NSCLC [1], [2]
LDK378 Drug Info Approved Non-small cell lung cancer [3], [4], [5]
AF-802 Drug Info Phase 2 Non-small cell lung cancer [6], [7]
AP26113 Drug Info Phase 2 Cancer [8], [9]
PF-06463922 Drug Info Phase 1/2 Cancer [10], [11]
RXDX 101 Drug Info Phase 1/2 Solid tumours [12]
TSR-011 Drug Info Phase 1/2 Non-small cell lung cancer [13]
X-396 Drug Info Phase 1/2 Advanced solid tumor [14]
ASP3026 Drug Info Phase 1 Late-stage B-cell lymphoma [15], [16]
Inhibitor AF-802 Drug Info [17]
AZD3463 Drug Info [18]
CEP-18050 Drug Info [18]
CEP-28122 Drug Info [18]
compound 15 Drug Info [19]
compound 25b Drug Info [20]
compound 5g Drug Info [21]
compound 5m Drug Info [21]
compound 5n Drug Info [21]
compound 8e Drug Info [22]
CRL-37212 Drug Info [18]
GSK-1838705A Drug Info [23]
NMS-E628 Drug Info [18]
PF-06463922 Drug Info [24]
RXDX 101 Drug Info [12]
TSR-011 Drug Info [25], [26]
X-396 Drug Info [27]
Modulator AP26113 Drug Info [28]
ASP3026 Drug Info [16]
Crizotinib Drug Info [5]
LDK378 Drug Info [4]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
KEGG Pathway Non-small cell lung cancer
WikiPathways Differentiation Pathway
References
REF 1(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 22011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
REF 32014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
REF 4(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 5Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 6ClinicalTrials.gov (NCT01871805) A Study of CH5424802/RO5424802 in Patients With ALK-Rearranged Non-Small Cell Lung Cancer. U.S. National Institutes of Health.
REF 7(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 8ClinicalTrials.gov (NCT02094573) A Phase 2, Multicenter, Randomized Study of AP26113. U.S. National Institutes of Health.
REF 9(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: 7741).
REF 10ClinicalTrials.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 11(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 12ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39.
REF 13ClinicalTrials.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 14ClinicalTrials.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 15ClinicalTrials.gov (NCT01401504) Study of an Investigational Drug, ASP3026, in Patients With Solid Tumors. U.S. National Institutes of Health.
REF 16(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 17CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011 May 17;19(5):679-90.
REF 18(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).
REF 19Discovery 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 20Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase. J Med Chem. 2012 May 24;55(10):4580-93.
REF 21Synthesis 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 22Design 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 23GSK1838705A 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 24PF-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 25Treatment of ALK-positive non-small cell lung cancer. Arch Pathol Lab Med. 2012 Oct;136(10):1201-4.
REF 26National Cancer Institute Drug Dictionary (drug id 757983).
REF 27Clinical pipeline report, company report or official report of Xcovery.
REF 28Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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