Target Information

Target General Infomation
Target ID
T82393
Former ID
TTDR00847
Target Name
ADAM 17
Gene Name
ADAM17
Synonyms
A disintegrin and metalloproteinase domain 17; CD156b antigen; Snake venom-like protease; TACE; TNF-alpha convertase; TNF-alpha converting enzyme; TNFalpha converting enzyme; ADAM17
Target Type
Clinical Trial
Disease Autoimmune diabetes [ICD10: E08-E13]
Breast cancer [ICD9: 174, 175; ICD10: C50]
Chronic obstructive pulmonary disease [ICD9: 490-492, 494-496; ICD10: J40-J44, J47]
Inflammatory bowel disease; Rheumatoid arthritis [ICD9: 555, 556, 710-719, 714; ICD10: K50, K51, M00-M25, M05-M06]
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06]
Function
Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein. Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT). Plays a role in the proteolytic processing of ACE2.
BioChemical Class
Peptidase
Target Validation
T82393
UniProt ID
P78536
EC Number
EC 3.4.24.86
Sequence
MRQSLLFLTSVVPFVLAPRPPDDPGFGPHQRLEKLDSLLSDYDILSLSNIQQHSVRKRDL
QTSTHVETLLTFSALKRHFKLYLTSSTERFSQNFKVVVVDGKNESEYTVKWQDFFTGHVV
GEPDSRVLAHIRDDDVIIRINTDGAEYNIEPLWRFVNDTKDKRMLVYKSEDIKNVSRLQS
PKVCGYLKVDNEELLPKGLVDREPPEELVHRVKRRADPDPMKNTCKLLVVADHRFYRYMG
RGEESTTTNYLIELIDRVDDIYRNTSWDNAGFKGYGIQIEQIRILKSPQEVKPGEKHYNM
AKSYPNEEKDAWDVKMLLEQFSFDIAEEASKVCLAHLFTYQDFDMGTLGLAYVGSPRANS
HGGVCPKAYYSPVGKKNIYLNSGLTSTKNYGKTILTKEADLVTTHELGHNFGAEHDPDGL
AECAPNEDQGGKYVMYPIAVSGDHENNKMFSNCSKQSIYKTIESKAQECFQERSNKVCGN
SRVDEGEECDPGIMYLNNDTCCNSDCTLKEGVQCSDRNSPCCKNCQFETAQKKCQEAINA
TCKGVSYCTGNSSECPPPGNAEDDTVCLDLGKCKDGKCIPFCEREQQLESCACNETDNSC
KVCCRDLSGRCVPYVDAEQKNLFLRKGKPCTVGFCDMNGKCEKRVQDVIERFWDFIDQLS
INTFGKFLADNIVGSVLVFSLIFWIPFSILVHCVDKKLDKQYESLSLFHPSNVEMLSSMD
SASVRIIKPFPAPQTPGRLQPAPVIPSAPAAPKLDHQRMDTIQEDPSTDSHMDEDGFEKD
PFPNSSTAAKSFEDLTDHPVTRSEKAASFKLQRQNRVDSKETEC
Drugs and Mode of Action
Drug(s) Apratastat Drug Info Phase 2 Rheumatoid arthritis [521616], [541616]
Aderbasib Drug Info Phase 1/2 Breast cancer [524760]
GW-3333 Drug Info Preclinical Chronic obstructive pulmonary disease [536223]
DPC-333 Drug Info Terminated Inflammatory bowel disease; Rheumatoid arthritis [536223], [541646]
Inhibitor 2-(4-bromophenylsulfonamido)-N-hydroxyacetamide Drug Info [530746]
2-(biphenyl-4-ylsulfonamido)-N-hydroxyacetamide Drug Info [530746]
Batimistat Drug Info [538112]
CH4474 Drug Info [535881]
DPC-333 Drug Info [536223]
GW-3333 Drug Info [536223]
IK-682 Drug Info [529692]
IK-862 Drug Info [529692]
IM-491 Drug Info [529165]
N-hydroxy-2-(4-methoxyphenylsulfonamido)acetamide Drug Info [530746]
N-hydroxy-3-(2-oxo-2H-chromen-3-yl)propanamide Drug Info [529102]
N-hydroxy-3-(6-methoxy-2-oxo-2H-chromen-3-yl) Drug Info [529102]
PKF-241-466 Drug Info [529876]
PKF-242-484 Drug Info [529876]
SL422 Drug Info [526113]
SR-973 Drug Info [528025]
TACE inhibitors Drug Info [543456]
TMI-05 Drug Info [527982]
Modulator Aderbasib Drug Info [1572591]
Apratastat Drug Info [528532], [536688]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Notch signaling pathway
Alzheimer&#039
s disease
Epithelial cell signaling in Helicobacter pylori infection
PANTHER Pathway Alzheimer disease-amyloid secretase pathway
Alzheimer disease-presenilin pathway
Notch signaling pathway
Pathway Interaction Database ErbB4 signaling events
TNF receptor signaling pathway
p75(NTR)-mediated signaling
Reactome Nuclear signaling by ERBB4
Collagen degradation
Regulated proteolysis of p75NTR
Activated NOTCH1 Transmits Signal to the Nucleus
Constitutive Signaling by NOTCH1 PEST Domain Mutants
Constitutive Signaling by NOTCH1 t(7
M1580_K2555) Translocation Mutant
Constitutive Signaling by NOTCH1 HD Domain Mutants
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
TNF signaling
Growth hormone receptor signaling
WikiPathways Notch Signaling Pathway
Copper homeostasis
Notch Signaling Pathway
Growth hormone receptor signaling
BDNF signaling pathway
Alzheimers Disease
Signalling by NGF
Extrinsic Pathway for Apoptosis
References
Ref 521616ClinicalTrials.gov (NCT00095342) Study Evaluating TMI-005 in Active Rheumatoid Arthritis. U.S. National Institutes of Health.
Ref 524760ClinicalTrials.gov (NCT02141451) INCB7839 With Rituximab After Autologous Hematopoietic Cell Transplantation for Diffuse Large B Cell Non-Hodgkin Lymphoma. U.S. National Institutes of Health.
Ref 536223Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
Ref 541616(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: 6482).
Ref 541646(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: 6509).
Ref
Ref 526113Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo. J Med Chem. 2001 Aug 2;44(16):2636-60.
Ref 527982Bioorg Med Chem Lett. 2006 Mar 15;16(6):1605-9. Epub 2006 Jan 19.Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates.
Ref 528025Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63. Epub 2006 Feb 10.Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors.
Ref 528532Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis. Curr Opin Investig Drugs. 2006 Nov;7(11):1014-9.
Ref 529102Bioorg Med Chem. 2008 Jan 1;16(1):530-5. Epub 2007 Sep 14.Chromen-based TNF-alpha converting enzyme (TACE) inhibitors: design, synthesis, and biological evaluation.
Ref 529165Bioorg Med Chem Lett. 2008 Jan 1;18(1):241-6. Epub 2007 Oct 30.Discovery of beta-benzamido hydroxamic acids as potent, selective, and orally bioavailable TACE inhibitors.
Ref 529692Bioorg Med Chem. 2008 Oct 1;16(19):8781-94. Epub 2008 Aug 29.Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge.
Ref 529876Bioorg Med Chem. 2009 Jan 15;17(2):444-59. Epub 2008 Dec 3.Current perspective of TACE inhibitors: a review.
Ref 530746J Med Chem. 2010 Mar 25;53(6):2622-35.Potent arylsulfonamide inhibitors of tumor necrosis factor-alpha converting enzyme able to reduce activated leukocyte cell adhesion molecule shedding in cancer cell models.
Ref 535881Tumour necrosis factor-alpha converting enzyme (TACE) activity in human colonic epithelial cells. Clin Exp Immunol. 2004 Jan;135(1):146-53.
Ref 536223Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
Ref 536688Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheumatol. 2008 Jun;4(6):300-9. Epub 2008 Apr 15.
Ref 538112The secretases that cleave angiotensin converting enzyme and the amyloid precursor protein are distinct from tumour necrosis factor-alpha convertase. FEBS Lett. 1998 Jul 10;431(1):63-5.
Ref 543456(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: 1662).
Ref 1572591Interpreting 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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