Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTNDSF4)

• DTT Name: Proto-oncogene c-Met (MET)
• Synonyms: Tyrosine-protein kinase Met; Scatter factor receptor; SF receptor; Met proto-oncogene tyrosine kinase; Hepatocyte growth factor receptor; HGF/SF receptor; HGF-SF receptor; HGF receptor; C-met; C-Met receptor tyrosine kinase
• Gene Name: MET
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: MET_HUMAN
• TTD ID: T40474
• EC Number: EC 2.7.10.1
• Sequence:
  MKAPAVLAPGILVLLFTLVQRSNGECKEALAKSEMNVNMKYQLPNFTAETPIQNVILHEH
  HIFLGATNYIYVLNEEDLQKVAEYKTGPVLEHPDCFPCQDCSSKANLSGGVWKDNINMAL
  VVDTYYDDQLISCGSVNRGTCQRHVFPHNHTADIQSEVHCIFSPQIEEPSQCPDCVVSAL
  GAKVLSSVKDRFINFFVGNTINSSYFPDHPLHSISVRRLKETKDGFMFLTDQSYIDVLPE
  FRDSYPIKYVHAFESNNFIYFLTVQRETLDAQTFHTRIIRFCSINSGLHSYMEMPLECIL
  TEKRKKRSTKKEVFNILQAAYVSKPGAQLARQIGASLNDDILFGVFAQSKPDSAEPMDRS
  AMCAFPIKYVNDFFNKIVNKNNVRCLQHFYGPNHEHCFNRTLLRNSSGCEARRDEYRTEF
  TTALQRVDLFMGQFSEVLLTSISTFIKGDLTIANLGTSEGRFMQVVVSRSGPSTPHVNFL
  LDSHPVSPEVIVEHTLNQNGYTLVITGKKITKIPLNGLGCRHFQSCSQCLSAPPFVQCGW
  CHDKCVRSEECLSGTWTQQICLPAIYKVFPNSAPLEGGTRLTICGWDFGFRRNNKFDLKK
  TRVLLGNESCTLTLSESTMNTLKCTVGPAMNKHFNMSIIISNGHGTTQYSTFSYVDPVIT
  SISPKYGPMAGGTLLTLTGNYLNSGNSRHISIGGKTCTLKSVSNSILECYTPAQTISTEF
  AVKLKIDLANRETSIFSYREDPIVYEIHPTKSFISGGSTITGVGKNLNSVSVPRMVINVH
  EAGRNFTVACQHRSNSEIICCTTPSLQQLNLQLPLKTKAFFMLDGILSKYFDLIYVHNPV
  FKPFEKPVMISMGNENVLEIKGNDIDPEAVKGEVLKVGNKSCENIHLHSEAVLCTVPNDL
  LKLNSELNIEWKQAISSTVLGKVIVQPDQNFTGLIAGVVSISTALLLLLGFFLWLKKRKQ
  IKDLGSELVRYDARVHTPHLDRLVSARSVSPTTEMVSNESVDYRATFPEDQFPNSSQNGS
  CRQVQYPLTDMSPILTSGDSDISSPLLQNTVHIDLSALNPELVQAVQHVVIGPSSLIVHF
  NEVIGRGHFGCVYHGTLLDNDGKKIHCAVKSLNRITDIGEVSQFLTEGIIMKDFSHPNVL
  SLLGICLRSEGSPLVVLPYMKHGDLRNFIRNETHNPTVKDLIGFGLQVAKGMKYLASKKF
  VHRDLAARNCMLDEKFTVKVADFGLARDMYDKEYYSVHNKTGAKLPVKWMALESLQTQKF
  TTKSDVWSFGVLLWELMTRGAPPYPDVNTFDITVYLLQGRRLLQPEYCPDPLYEVMLKCW
  HPKAEMRPSFSELVSRISAIFSTFIGEHYVHVNATYVNVKCVAPYPSLLSSEDNADDEVD
  TRPASFWETS
• Function: Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. May regulate cortical bone osteogenesis. Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand.
• KEGG Pathway:
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  Cytokine-cytokine receptor interaction (hsa04060)
  Endocytosis (hsa04144)
  PI3K-Akt signaling pathway (hsa04151)
  Axon guidance (hsa04360)
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  Bacterial invasion of epithelial cells (hsa05100)
  Epithelial cell signaling in Helicobacter pylori infection (hsa05120)
  Malaria (hsa05144)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
  Renal cell carcinoma (hsa05211)
  Melanoma (hsa05218)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway: Sema4D mediated inhibition of cell attachment and migration (R-HSA-416550)

Molecular Interaction Atlas (MIA) of This DTT

5 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Amivantamab	DMZ7AMY	Non-small-cell lung cancer	2C25	Approved	[2]
Cabozantinib	DMIYDT4	Medullary thyroid gland carcinoma		Approved	[3]
Capmatinib	DMYCXKL	Non-small-cell lung cancer	2C25.Y	Approved	[4]
Crizotinib	DM4F29C	Non-small-cell lung cancer	2C25.Y	Approved	[1]
Tepotinib	DMUQ0E8	Non-small-cell lung cancer	2C25	Approved	[5]

42 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Beperminogene perplasmid	DM6RWBN	Critical limb ischemia	BD4Y	Phase 3	[6]
RG3638	DMTQJE0	Gastric adenocarcinoma	2B72	Phase 3	[7]
Savolitinib	DMALFKX	Renal cell carcinoma	2C90	Phase 3	[8]
Tivantinib	DMNVP8Q	Hepatocellular carcinoma	2C12.02	Phase 3	[9]
MGCD516	DM752PU	Solid tumour/cancer	2A00-2F9Z	Phase 2/3	[7]
AMG 208	DMPQHOR	Solid tumour/cancer	2A00-2F9Z	Phase 2	[10]
AMG 337	DMIOUEY	Clear cell sarcoma	2A60-2C35	Phase 2	[11]
APL-101	DMP0LST	Non-small-cell lung cancer	2C25	Phase 2	[12]
CMX-2043	DMPSCVY	Cardiac disease	BA00-BE2Z	Phase 2	[13]
Emibetuzumab	DMT4MKF	Solid tumour/cancer	2A00-2F9Z	Phase 2	[14]
HM-5016504	DMLQDBH	Solid tumour/cancer	2A00-2F9Z	Phase 2	[7]
LY-2875358	DMQV1OU	Solid tumour/cancer	2A00-2F9Z	Phase 2	[15]
LY2801653	DM0KJDY	Biliary tract cancer	2C17	Phase 2	[16]
SAR-125844	DMJ34G6	Solid tumour/cancer	2A00-2F9Z	Phase 2	[17]
Telisotuzumab vedotin	DM8UCNK	Non-small-cell lung cancer	2C25.Y	Phase 2	[18]
XL880	DMHJTR2	Breast cancer	2C60-2C65	Phase 2	[19]
Anti-C-met CAR-T cells	DMV5H0S	Colorectal cancer	2B91.Z	Phase 1/2	[20]
BMS-777607	DMGM7QD	N. A.	N. A.	Phase 1/2	[21]
ChronSeal	DM90BUD	Fibrosis	GA14-GC01	Phase 1/2	[22]
MK-2461	DM21WBH	Alzheimer disease	8A20	Phase 1/2	[23]
Sym015	DM9B7Z5	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[8]
ABBV-399	DMQGPRE	Solid tumour/cancer	2A00-2F9Z	Phase 1	[14]
ABT-700	DMVLPRT	Advanced solid tumour	2A00-2F9Z	Phase 1	[24]
Altiratinib	DMUJCBT	Solid tumour/cancer	2A00-2F9Z	Phase 1	[25]
Autologous T Cells Expressing MET scFv CAR	DMZ763A	Melanoma	2C30	Phase 1	[26]
AZD9592	DMDPM67	Aggressive cancer	2A00-2F9Z	Phase 1	[27]
BPI-9016 M	DMNY0U5	Solid tumour/cancer	2A00-2F9Z	Phase 1	[28]
C-Met/PD-L1 CAR-T Cell	DMHBNKP	Hepatocellular carcinoma	2C12.02	Phase 1	[29]
CBT-101	DMOTLN4	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
E-7050	DMDOCNW	Head and neck cancer	2D42	Phase 1	[30]
EMD-1204831	DM38JZU	Solid tumour/cancer	2A00-2F9Z	Phase 1	[31]
Hepapoietin	DMM7VOB	Liver disease	DB90-BD99	Phase 1	[32]
JNJ-38877605	DMDIPW8	Solid tumour/cancer	2A00-2F9Z	Phase 1	[33]
LY3164530	DM9RTXM	Advanced cancer	2A00-2F9Z	Phase 1	[34]
MK-8033	DMA1EDN	Solid tumour/cancer	2A00-2F9Z	Phase 1	[35]
PF-4217903	DMU2A6D	Solid tumour/cancer	2A00-2F9Z	Phase 1	[36]
REGN5093	DM3720L	Non-small-cell lung cancer	2C25.Y	Phase 1	[37]
RXDX-106	DM6NVTR	Solid tumour/cancer	2A00-2F9Z	Phase 1	[38]
SGX523	DM3RSMF	Solid tumour/cancer	2A00-2F9Z	Phase 1	[39]
TPX-0022	DMC2IJN	Solid tumour/cancer	2A00-2F9Z	Phase 1	[40]
TR1801-ADC	DMGC2AT	Solid tumour/cancer	2A00-2F9Z	Phase 1	[41]
XL092	DM3LRAC	Solid tumour/cancer	2A00-2F9Z	Phase 1	[42]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Mteron-F1	DMCZW4Q	Mucositis	CA00	Preclinical	[43]
NPS-1034	DMOGRWB	Solid tumour/cancer	2A00-2F9Z	Preclinical	[44]

27 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-(2-nitrophenethyl)-1H-pyrrolo[3,2-b]pyridine	DMR12KP	Discovery agent	N.A.	Investigative	[45]
1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine	DM8APLN	Discovery agent	N.A.	Investigative	[45]
1-benzyl-1H-pyrrolo[3,2-b]pyridine	DMEVSFY	Discovery agent	N.A.	Investigative	[45]
3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine	DMN1DWF	Discovery agent	N.A.	Investigative	[45]
ALD-805	DMQXO5G	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
ALD-806	DMWBKH1	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
AM7	DMYVQFN	Discovery agent	N.A.	Investigative	[46]
Anti-cMET mab	DM2X1SG	Discovery agent	N.A.	Investigative	[7]
APS-3010	DM8DOBG	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
BAY-85-3474	DMW625B	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
BMS-536924	DMXJB4N	Discovery agent	N.A.	Investigative	[47]
CMET Avimer polypeptides	DM6PFG0	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
DP-3590	DMFZML9	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
GE-137	DMB813H	Discovery agent	N.A.	Investigative	[48]
HuMax-cMet	DM8AG5R	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
LA-480	DMP1V8Y	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
mab 224G11	DM1ICOW	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
PF-00614435	DMWL9CU	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
PHA-665752	DMCGX9U	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
PMID21123062C27	DMVPW1G	Discovery agent	N.A.	Investigative	[49]
PMID21967808CR-16	DMCOHKU	Discovery agent	N.A.	Investigative	[50]
PMID24210504C1o	DM4LEUT	Discovery agent	N.A.	Investigative	[51]
PRS-110	DMB923H	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
RP-1040	DMP2EDX	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
SU11274	DMASP9Z	Discovery agent	N.A.	Investigative	[52]
TP-801	DM4WTCE	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
YH013	DMQ0474	Aggressive cancer	2A00-2F9Z	Investigative	[53]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	1.08E-03	-0.24	-0.4
Lung cancer	2C82	Lung tissue	2.48E-02	-0.51	-0.69
Thyroid cancer	2C82	Thyroid	2.71E-34	1.52	2.67
Renal cancer	2C82	Kidney	2.88E-02	0.51	0.97
Head and neck cancer	2C82	Head and neck tissue	6.16E-01	0.31	0.37
Liver cancer	2C82	Liver tissue	9.24E-01	-0.08	-0.08

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [2] Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR-MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion-Driven NSCLC. Cancer Discov. 2020 Aug;10(8):1194-1209.
• [3] Clinical pipeline report, company report or official report of Exelixis (2011).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021
• [6] Beperminogene perplasmid for the treatment of critical limb ischemia. Expert Rev Cardiovasc Ther. 2014 Oct;12(10):1145-56.
• [7] 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: 1815).
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] 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: 7948).
• [10] A first-in-human study of AMG 208, an oral MET inhibitor, in adult patients with advanced solid tumors. Oncotarget. 2015 Jul 30;6(21):18693-706.
• [11] J Clin Oncol 32:5s, 2014 (suppl; abstr 2508).
• [12] Clinical pipeline report, company report or official report of Apollomics.
• [13] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [14] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [15] Clinical pipeline report, company report or official report of Eli Lilly.
• [16] Clinical pipeline report, company report or official report of Eli Lilly.
• [17] The selective intravenous inhibitor of the MET tyrosine kinase SAR125844 inhibits tumor growth in MET-amplified cancer. Mol Cancer Ther. 2015 Feb;14(2):384-94.
• [18] Clinical pipeline report, company report or official report of AbbVie.
• [19] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [20] ClinicalTrials.gov (NCT03638206) Autologous CAR-T/TCR-T Cell Immunotherapy for Malignancies
• [21] Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607... J Med Chem. 2009 Mar 12;52(5):1251-4.
• [22] Clinical pipeline report, company report or official report of Kringle Pharma.
• [23] MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
• [24] J Clin Oncol 32:5s, 2014 (suppl; abstr 2507).
• [25] Clinical pipeline report, company report or official report of Deciphera Pharmaceuticals.
• [26] ClinicalTrials.gov (NCT03060356) Autologous T Cells Expressing MET scFv CAR (RNA CART-cMET)
• [27] Clinical pipeline report, company report or official report of AstraZeneca
• [28] First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer. J Hematol Oncol. 2020 Jan 16;13(1):6.
• [29] ClinicalTrials.gov (NCT03672305) Clinical Study on the Efficacy and Safety of c-Met/PD-L1 CAR-T Cell Injection in the Treatment of HCC
• [30] E7050: a dual c-Met and VEGFR-2 tyrosine kinase inhibitor promotes tumor regression and prolongs survival in mouse xenograft models. Cancer Sci. 2010 Jan;101(1):210-5.
• [31] 2012 ASCO Annual Meeting.
• [32] Pharmacokinetics and biochemical effects of hepapoietin in patients with chronic liver disease. Alimentary Pharmacology & Therapeutics Volume 16, Issue 2, pages 235-242, February 2002.
• [33] The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation. Clin Cancer Res. 2015 May 15;21(10):2297-304.
• [34] Bispecific antibodies rise again. Nat Rev Drug Discov. 2014 Nov;13(11):799-801.
• [35] A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth. Oncol Rep. 2013 May;29(5):2011-8.
• [36] Sensitivity of selected human tumor models to PF-04217903, a novel selective c-Met kinase inhibitor. Mol Cancer Ther. 2012 Apr;11(4):1036-47.
• [37] Clinical pipeline report, company report or official report of Regeneron Pharmaceuticals.
• [38] National Cancer Institute Drug Dictionary (drug name RXDX106).
• [39] CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.
• [40] Clinical pipeline report, company report or official report of Turning Point Therapeutics.
• [41] TR1801-ADC: a highly potent cMet antibody-drug conjugate with high activity in patient-derived xenograft models of solid tumors. Mol Oncol. 2020 Jan;14(1):54-68.
• [42] Clinical pipeline report, company report or official report of Exelixis.
• [43] Emerging drugs for chemotherapy-induced mucositis. Expert Opin Emerg Drugs. 2008 Sep;13(3):511-22.
• [44] NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants. Invest New Drugs. 2014 Jun;32(3):389-99.
• [45] Discovery of 4-azaindoles as novel inhibitors of c-Met kinase. Bioorg Med Chem Lett. 2009 May 15;19(10):2780-4.
• [46] c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations. J Biol Chem. 2008 Feb 1;283(5):2675-83.
• [47] Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitum... J Med Chem. 2005 Sep 8;48(18):5639-43.
• [48] Detection of colorectal polyps in humans using an intravenously administered fluorescent peptide targeted against c-Met. Nat Med. 2015 Aug;21(8):955-61.
• [49] Fused bicyclic derivatives of 2,4-diaminopyrimidine as c-Met inhibitors. Bioorg Med Chem Lett. 2011 Jan 1;21(1):164-7.
• [50] Improvement in oral bioavailability of 2,4-diaminopyrimidine c-Met inhibitors by incorporation of a 3-amidobenzazepin-2-one group. Bioorg Med Chem. 2011 Nov 1;19(21):6274-84.
• [51] Design and synthesis of novel 3-(benzo[d]oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine derivatives as selective G-protein-coupled receptor kinase-2 and -5 inhibitors. Bioorg Med Chem Lett. 2013 Dec 15;23(24):6711-6.
• [52] Potent and selective inhibitors of the Met [hepatocyte growth factor/scatter factor (HGF/SF) receptor] tyrosine kinase block HGF/SF-induced tumor cell growth and invasion. Mol Cancer Ther. 2003 Nov;2(11):1085-92.
• [53] Clinical pipeline report, company report or official report of Biocytogen