Target Information
| Target General Information | Top | |||||
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| Target ID |
T56418
(Former ID: TTDI02271)
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| Target Name |
ALK tyrosine kinase receptor (ALK)
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| Synonyms |
CD246; Anaplastic lymphoma kinase
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| Gene Name |
ALK
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Lung cancer [ICD-11: 2C25] | |||||
| 2 | Mature T-cell lymphoma [ICD-11: 2A90] | |||||
| 3 | Non-small-cell lung cancer [ICD-11: 2C25] | |||||
| 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.
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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 Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 5 Approved Drugs | + | ||||
| 1 | Brigatinib | Drug Info | Approved | Non-small-cell lung cancer | [3] | |
| 2 | Ceritinib | Drug Info | Approved | Non-small-cell lung cancer | [4], [5], [6], [7] | |
| 3 | Crizotinib | Drug Info | Approved | Non-small-cell lung cancer | [8], [9] | |
| 4 | Entrectinib | Drug Info | Approved | Non-small-cell lung cancer | [10] | |
| 5 | Lorlatinib | Drug Info | Approved | Non-small-cell lung cancer | [11] | |
| Clinical Trial Drug(s) | [+] 6 Clinical Trial Drugs | + | ||||
| 1 | Ensartinib | Drug Info | Phase 3 | Non-small-cell lung cancer | [12] | |
| 2 | AP26113 | Drug Info | Phase 2 | Solid tumour/cancer | [13], [14] | |
| 3 | PF-06463922 | Drug Info | Phase 2 | Non-small-cell lung cancer | [15] | |
| 4 | TSR-011 | Drug Info | Phase 1/2 | Non-small-cell lung cancer | [16] | |
| 5 | X-396 | Drug Info | Phase 1/2 | Advanced solid tumour | [17] | |
| 6 | ASP3026 | Drug Info | Phase 1 | Diffuse large B-cell lymphoma | [18], [19] | |
| Patented Agent(s) | [+] 2 Patented Agents | + | ||||
| 1 | Benzimidazole derivative 6 | Drug Info | Patented | Solid tumour/cancer | [20] | |
| 2 | PMID28270010-Compound-Figure21-b | Drug Info | Patented | Brain metastases | [20] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 22 Inhibitor drugs | + | ||||
| 1 | Brigatinib | Drug Info | [21] | |||
| 2 | Entrectinib | Drug Info | [10] | |||
| 3 | Lorlatinib | Drug Info | [11] | |||
| 4 | Ensartinib | Drug Info | [12] | |||
| 5 | PF-06463922 | Drug Info | [23] | |||
| 6 | TSR-011 | Drug Info | [24], [25] | |||
| 7 | X-396 | Drug Info | [26] | |||
| 8 | 1,2,4-triazolo[1,5a]pyridine derivative 2 | Drug Info | [27] | |||
| 9 | Benzimidazole derivative 6 | Drug Info | [20] | |||
| 10 | Carboxamide derivative 4 | Drug Info | [28] | |||
| 11 | PMID28270010-Compound-Figure21-b | Drug Info | [20] | |||
| 12 | AZD3463 | Drug Info | [29] | |||
| 13 | CEP-18050 | Drug Info | [29] | |||
| 14 | CEP-28122 | Drug Info | [29] | |||
| 15 | CRL-37212 | Drug Info | [29] | |||
| 16 | GSK-1838705A | Drug Info | [30] | |||
| 17 | PMID20483621C5g | Drug Info | [31] | |||
| 18 | PMID20483621C5m | Drug Info | [31] | |||
| 19 | PMID20483621C5n | Drug Info | [31] | |||
| 20 | PMID22564207C25b | Drug Info | [32] | |||
| 21 | PMID24432909C8e | Drug Info | [33] | |||
| 22 | PMID24900237C15 | Drug Info | [34] | |||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | Ceritinib | Drug Info | [4] | |||
| 2 | Crizotinib | Drug Info | [6] | |||
| 3 | AP26113 | Drug Info | [22] | |||
| 4 | ASP3026 | Drug Info | [18] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Ceritinib | Ligand Info | |||||
| Structure Description | Crystal Structure of Anaplastic Lymphoma Kinase Complexed with LDK378 | PDB:4MKC | ||||
| Method | X-ray diffraction | Resolution | 2.01 Å | Mutation | Yes | [35] |
| PDB Sequence |
NPNYCFAGKT
1102 SSISDLKEVP1112 RKNITLIRGL1122 GHGAFGEVYE1132 GQVSSPLQVA1148 VKTLPEVCSE 1158 QDELDFLMEA1168 LIISKFNHQN1178 IVRCIGVSLQ1188 SLPRFILLEL1198 MAGGDLKSFL 1208 RETRPRPSQP1218 SSLAMLDLLH1228 VARDIACGCQ1238 YLEENHFIHR1248 DIAARNCLLT 1258 CPGPGRVAKI1268 GDFGMARDIY1278 RAGYYRKGGC1288 AMLPVKWMPP1298 EAFMEGIFTS 1308 KTDTWSFGVL1318 LWEIFSLGYM1328 PYPSKSNQEV1338 LEFVTSGGRM1348 DPPKNCPGPV 1358 YRIMTQCWQH1368 QPEDRPNFAI1378 ILERIEYCTQ1388 DPDVINTALP1398 IEY |
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LEU1122
3.503
GLY1123
3.981
HIS1124
3.492
GLY1125
3.331
ALA1126
4.537
VAL1130
3.712
GLU1132
4.030
ALA1148
3.402
LYS1150
3.431
VAL1180
4.865
LEU1196
3.420
GLU1197
3.218
LEU1198
3.923
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| Ligand Name: Alectinib | Ligand Info | |||||
| Structure Description | X-ray crystal structure of human anaplastic lymphoma kinase in complex with CH5424802 | PDB:3AOX | ||||
| Method | X-ray diffraction | Resolution | 1.75 Å | Mutation | No | [1] |
| PDB Sequence |
STIMTDYNPN
1095 YCFAGKTSSI1105 SDLKEVPRKN1115 ITLIRGLGGE1129 VYEGQVSPLQ1146 VAVKTLPEVC 1156 SEQDELDFLM1166 EALIISKFNH1176 QNIVRCIGVS1186 LQSLPRFILL1196 ELMAGGDLKS 1206 FLRETRPRPS1216 QPSSLAMLDL1226 LHVARDIACG1236 CQYLEENHFI1246 HRDIAARNCL 1256 LTCPGPGRVA1266 KIGDFGMARD1276 IYRACAMLPV1293 KWMPPEAFME1303 GIFTSKTDTW 1313 SFGVLLWEIF1323 SLGYMPYPSK1333 SNQEVLEFVT1343 SGGRMDPPKN1353 CPGPVYRIMT 1363 QCWQHQPEDR1373 PNFAIILERI1383 EYCTQDPDVI1393 NTALPIEY
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ARG1120
3.387
LEU1122
3.678
GLY1123
4.027
VAL1130
4.015
GLU1132
4.440
ALA1148
3.479
LYS1150
3.817
GLU1167
4.606
ILE1171
4.969
VAL1180
3.865
LEU1196
3.565
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Degree | 10 | Degree centrality | 1.07E-03 | Betweenness centrality | 4.76E-04 |
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| Closeness centrality | 2.29E-01 | Radiality | 1.40E+01 | Clustering coefficient | 2.00E-01 |
| Neighborhood connectivity | 4.48E+01 | Topological coefficient | 1.80E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Drug Resistance Mutation (DRM) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Non-small cell lung cancer | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Differentiation Pathway | |||||
| References | Top | |||||
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| 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 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019 | |||||
| REF 11 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
| REF 12 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 13 | 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 14 | ClinicalTrials.gov (NCT02094573) A Phase 2, Multicenter, Randomized Study of AP26113. U.S. National Institutes of Health. | |||||
| REF 15 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 16 | 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 17 | 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 18 | 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 19 | ClinicalTrials.gov (NCT01401504) Study of an Investigational Drug, ASP3026, in Patients With Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 20 | Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751. | |||||
| REF 21 | 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85. | |||||
| REF 22 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
| REF 23 | 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 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. | |||||
| REF 35 | The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 2014 Jun;4(6):662-673. | |||||
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