Target General Infomation
Target ID
T56418 (Former ID: TTDI02271)
Target Name
ALK tyrosine kinase receptor (ALK)
Synonyms
CD246; Anaplastic lymphoma kinase
Gene Name
ALK
Target Type
Successful target
[1]
Disease [+] 2 Target-related Diseases +
1 Lung cancer [ICD-11: 2C25]
2 Mature T-cell lymphoma [ICD-11: 2A90]
Function
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. 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.
BioChemical Class
Kinase
UniProt ID
ALK_HUMAN
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
Drugs and Modes of Action
Approved Drug(s) [+] 5 Approved Drugs +
1 Alectinib Drug Info Approved Lung cancer [2]
2 Brigatinib Drug Info Approved Non-small-cell lung cancer [3]
3 Ceritinib Drug Info Approved Non-small-cell lung cancer [4], [5], [6], [7]
4 Crizotinib Drug Info Approved Non-small-cell lung cancer [8], [9]
5 Lorlatinib Drug Info Approved Non-small-cell lung cancer [10]
Clinical Trial Drug(s) [+] 8 Clinical Trial Drugs +
1 Ensartinib Drug Info Phase 3 Non-small-cell lung cancer [11]
2 AP26113 Drug Info Phase 2 Solid tumour/cancer [12], [13]
3 PF-06463922 Drug Info Phase 2 Non-small-cell lung cancer [14]
4 RXDX 101 Drug Info Phase 2 Colorectal cancer [14]
5 TPX-0005 Drug Info Phase 1/2 Solid tumour/cancer [11]
6 TSR-011 Drug Info Phase 1/2 Non-small-cell lung cancer [15]
7 X-396 Drug Info Phase 1/2 Advanced solid tumour [16]
8 ASP3026 Drug Info Phase 1 Diffuse large B-cell lymphoma [17], [18]
Patented Agent(s) [+] 2 Patented Agents +
1 Benzimidazole derivative 6 Drug Info Patented Solid tumour/cancer [19]
2 PMID28270010-Compound-Figure21-b Drug Info Patented Brain metastases [19]
Mode of Action [+] 2 Modes of Action +
Inhibitor [+] 25 Inhibitor drugs +
1 Alectinib Drug Info [1]
2 Brigatinib Drug Info [20]
3 Lorlatinib Drug Info [10]
4 Ensartinib Drug Info [11]
5 PF-06463922 Drug Info [22]
6 RXDX 101 Drug Info [23]
7 TPX-0005 Drug Info [11]
8 TSR-011 Drug Info [24], [25]
9 X-396 Drug Info [26]
10 1,2,4-triazolo[1,5a]pyridine derivative 2 Drug Info [27]
11 Benzimidazole derivative 6 Drug Info [19]
12 Carboxamide derivative 4 Drug Info [28]
13 PMID28270010-Compound-Figure21-b Drug Info [19]
14 AZD3463 Drug Info [29]
15 CEP-18050 Drug Info [29]
16 CEP-28122 Drug Info [29]
17 CRL-37212 Drug Info [29]
18 GSK-1838705A Drug Info [30]
19 NMS-E628 Drug Info [29]
20 PMID20483621C5g Drug Info [31]
21 PMID20483621C5m Drug Info [31]
22 PMID20483621C5n Drug Info [31]
23 PMID22564207C25b Drug Info [32]
24 PMID24432909C8e Drug Info [33]
25 PMID24900237C15 Drug Info [34]
Modulator [+] 4 Modulator drugs +
1 Ceritinib Drug Info [4]
2 Crizotinib Drug Info [6]
3 AP26113 Drug Info [21]
4 ASP3026 Drug Info [17]
Target Regulators
Target-regulating microRNAs
Target-interacting Proteins
Target Profiles in Patients
Target Expression
 Profile (TEP)
Drug Resistance
 Mutation (DRM)
Target Affiliated Biological Pathways
KEGG Pathway [+] 1 KEGG Pathways +
1 Non-small cell lung cancer
WikiPathways [+] 1 WikiPathways +
1 Differentiation Pathway
References
REF 1 CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011 May 17;19(5):679-90.
REF 2 Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017 Jul 1;390(10089):29-39.
REF 3 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2018
REF 4 URL: 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 5 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
REF 6 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 7 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
REF 8 URL: 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 9 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
REF 10 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
REF 11 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 12 URL: 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 13 ClinicalTrials.gov (NCT02094573) A Phase 2, Multicenter, Randomized Study of AP26113. U.S. National Institutes of Health.
REF 14 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 15 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 16 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 17 URL: 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 18 ClinicalTrials.gov (NCT01401504) Study of an Investigational Drug, ASP3026, in Patients With Solid Tumors. U.S. National Institutes of Health.
REF 19 Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751.
REF 20 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
REF 21 Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
REF 22 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 23 ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39.
REF 24 Treatment of ALK-positive non-small cell lung cancer. Arch Pathol Lab Med. 2012 Oct;136(10):1201-4.
REF 25 National Cancer Institute Drug Dictionary (drug id 757983).
REF 26 Clinical pipeline report, company report or official report of Xcovery.
REF 27 Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 1.Expert Opin Ther Pat. 2017 Feb;27(2):127-143.
REF 28 RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99.
REF 29 URL: 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 30 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 31 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 32 Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase. J Med Chem. 2012 May 24;55(10):4580-93.
REF 33 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 34 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.

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