Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTPMQSO)

• DTT Name: ALK tyrosine kinase receptor (ALK)
• Synonyms: CD246; Anaplastic lymphoma kinase
• Gene Name: ALK
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: ALK_HUMAN
• TTD ID: T56418
• 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
• 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.
• KEGG Pathway: Non-small cell lung cancer (hsa05223)
• 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 DTT

7 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Alectinib	DMP1I6Y	Lung cancer	2C25.0	Approved	[1]
Brigatinib	DM7W94S	Anaplastic large cell lymphoma	2A90.A	Approved	[2]
Ceritinib	DMB920Z	Non-small-cell lung cancer	2C25.Y	Approved	[3]
Crizotinib	DM4F29C	Non-small-cell lung cancer	2C25.Y	Approved	[4]
Entrectinib	DMMPTLH	Non-small-cell lung cancer	2C25	Approved	[5]
Lorlatinib	DMICDLV	Non-small-cell lung cancer	2C25.Y	Approved	[6]
Repotrectinib	DM9FB2T	Non-small-cell lung cancer	2C25	Approved	[7]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ensartinib	DMIKDCQ	Non-small-cell lung cancer	2C25.Y	Phase 3	[7]
AP26113	DMYBQEF	Solid tumour/cancer	2A00-2F9Z	Phase 2	[8]
PF-06463922	DMKM7EW	Non-small-cell lung cancer	2C25.Y	Phase 2	[9]
TSR-011	DMFOR9Y	Non-small-cell lung cancer	2C25.Y	Phase 1/2	[10]
X-396	DMZ9VCF	Advanced solid tumour	2A00-2F9Z	Phase 1/2	[11]
ASP3026	DMW72NJ	Diffuse large B-cell lymphoma	2A81	Phase 1	[12]

4 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1,2,4-triazolo[1,5a]pyridine derivative 2	DMZFILT	N. A.	N. A.	Patented	[13]
Benzimidazole derivative 6	DMV7TMB	Solid tumour/cancer	2A00-2F9Z	Patented	[14]
Carboxamide derivative 4	DMU5GKC	N. A.	N. A.	Patented	[15]
PMID28270010-Compound-Figure21-b	DM6IYAT	Brain metastases	2D50	Patented	[14]

12 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD3463	DMAX9C3	Discovery agent	N.A.	Investigative	[16]
CEP-18050	DMCIOSM	Lymphoma	2A80-2A86	Investigative	[16]
CEP-28122	DMAY04M	Solid tumour/cancer	2A00-2F9Z	Investigative	[16]
CRL-37212	DMERKU2	Solid tumour/cancer	2A00-2F9Z	Investigative	[16]
DLX-521	DMPD2XF	Discovery agent	N.A.	Investigative	[16]
GSK-1838705A	DM4HLK3	Discovery agent	N.A.	Investigative	[17]
PMID20483621C5g	DMQ918T	Discovery agent	N.A.	Investigative	[18]
PMID20483621C5m	DML6OZR	Discovery agent	N.A.	Investigative	[18]
PMID20483621C5n	DM2BUKP	Discovery agent	N.A.	Investigative	[18]
PMID22564207C25b	DMBMYKQ	Discovery agent	N.A.	Investigative	[19]
PMID24432909C8e	DMEGAZS	Discovery agent	N.A.	Investigative	[20]
PMID24900237C15	DM6TFPY	Discovery agent	N.A.	Investigative	[21]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	7.19E-15	0.18	0.61

References

• [1] CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011 May 17;19(5):679-90.
• [2] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [3] 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).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [6] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [9] 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.
• [10] Treatment of ALK-positive non-small cell lung cancer. Arch Pathol Lab Med. 2012 Oct;136(10):1201-4.
• [11] Clinical pipeline report, company report or official report of Xcovery.
• [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: 7740).
• [13] 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.
• [14] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751.
• [15] RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99.
• [16] 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).
• [17] 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.
• [18] 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.
• [19] Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase. J Med Chem. 2012 May 24;55(10):4580-93.
• [20] 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.
• [21] 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.