Target Information
| Target General Information | Top | |||||
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| Target ID |
T82393
(Former ID: TTDR00847)
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| Target Name |
TNF alpha converting enzyme (ADAM17)
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| Synonyms |
TNFalpha converting enzyme; TNF-alpha-converting enzyme; TNF-alpha converting enzyme; TNF-alpha convertase; TACE; Snake venom-like protease; Disintegrin and metalloproteinase domain-containing protein 17; CSVP; CD156b antigen; CD156b; ADAM 17; A disintegrin and metalloproteinase domain 17
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| Gene Name |
ADAM17
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Rheumatoid arthritis [ICD-11: FA20] | |||||
| 2 | Breast cancer [ICD-11: 2C60-2C6Y] | |||||
| Function |
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. Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain. Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3. Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.24.86
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| Sequence |
MRQSLLFLTSVVPFVLAPRPPDDPGFGPHQRLEKLDSLLSDYDILSLSNIQQHSVRKRDL
QTSTHVETLLTFSALKRHFKLYLTSSTERFSQNFKVVVVDGKNESEYTVKWQDFFTGHVV GEPDSRVLAHIRDDDVIIRINTDGAEYNIEPLWRFVNDTKDKRMLVYKSEDIKNVSRLQS PKVCGYLKVDNEELLPKGLVDREPPEELVHRVKRRADPDPMKNTCKLLVVADHRFYRYMG RGEESTTTNYLIELIDRVDDIYRNTSWDNAGFKGYGIQIEQIRILKSPQEVKPGEKHYNM AKSYPNEEKDAWDVKMLLEQFSFDIAEEASKVCLAHLFTYQDFDMGTLGLAYVGSPRANS HGGVCPKAYYSPVGKKNIYLNSGLTSTKNYGKTILTKEADLVTTHELGHNFGAEHDPDGL AECAPNEDQGGKYVMYPIAVSGDHENNKMFSNCSKQSIYKTIESKAQECFQERSNKVCGN SRVDEGEECDPGIMYLNNDTCCNSDCTLKEGVQCSDRNSPCCKNCQFETAQKKCQEAINA TCKGVSYCTGNSSECPPPGNAEDDTVCLDLGKCKDGKCIPFCEREQQLESCACNETDNSC KVCCRDLSGRCVPYVDAEQKNLFLRKGKPCTVGFCDMNGKCEKRVQDVIERFWDFIDQLS INTFGKFLADNIVGSVLVFSLIFWIPFSILVHCVDKKLDKQYESLSLFHPSNVEMLSSMD SASVRIIKPFPAPQTPGRLQPAPVIPSAPAAPKLDHQRMDTIQEDPSTDSHMDEDGFEKD PFPNSSTAAKSFEDLTDHPVTRSEKAASFKLQRQNRVDSKETEC Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T91MWA | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | Apratastat | Drug Info | Phase 2 | Rheumatoid arthritis | [2], [3] | |
| 2 | Aderbasib | Drug Info | Phase 1/2 | Breast cancer | [4] | |
| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | GW-3333 | Drug Info | Preclinical | Chronic obstructive pulmonary disease | [5] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | DPC-333 | Drug Info | Terminated | Rheumatoid arthritis | [5], [6] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | Apratastat | Drug Info | [1], [7], [8] | |||
| 2 | Aderbasib | Drug Info | [9] | |||
| Inhibitor | [+] 15 Inhibitor drugs | + | ||||
| 1 | GW-3333 | Drug Info | [5] | |||
| 2 | DPC-333 | Drug Info | [5] | |||
| 3 | 2-(4-bromophenylsulfonamido)-N-hydroxyacetamide | Drug Info | [10] | |||
| 4 | 2-(biphenyl-4-ylsulfonamido)-N-hydroxyacetamide | Drug Info | [10] | |||
| 5 | Batimistat | Drug Info | [11] | |||
| 6 | CH4474 | Drug Info | [12] | |||
| 7 | IK-862 | Drug Info | [13] | |||
| 8 | IM-491 | Drug Info | [14] | |||
| 9 | N-hydroxy-2-(4-methoxyphenylsulfonamido)acetamide | Drug Info | [10] | |||
| 10 | N-hydroxy-3-(2-oxo-2H-chromen-3-yl)propanamide | Drug Info | [15] | |||
| 11 | N-hydroxy-3-(6-methoxy-2-oxo-2H-chromen-3-yl) | Drug Info | [15] | |||
| 12 | PKF-241-466 | Drug Info | [16] | |||
| 13 | PKF-242-484 | Drug Info | [16] | |||
| 14 | SL422 | Drug Info | [17] | |||
| 15 | SR-973 | Drug Info | [18] | |||
| 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 | |||||
|---|---|---|---|---|---|---|
| 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) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| Target QSAR Model | ||||||
| References | Top | |||||
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| REF 1 | Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates. Bioorg Med Chem Lett. 2006 Mar 15;16(6):1605-9. | |||||
| REF 2 | 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: 6482). | |||||
| REF 3 | ClinicalTrials.gov (NCT00095342) Study Evaluating TMI-005 in Active Rheumatoid Arthritis. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.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 5 | Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91. | |||||
| REF 6 | 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: 6509). | |||||
| REF 7 | Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheumatol. 2008 Jun;4(6):300-9. | |||||
| REF 8 | Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis. Curr Opin Investig Drugs. 2006 Nov;7(11):1014-9. | |||||
| REF 9 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
| REF 10 | Potent arylsulfonamide inhibitors of tumor necrosis factor-alpha converting enzyme able to reduce activated leukocyte cell adhesion molecule sheddi... J Med Chem. 2010 Mar 25;53(6):2622-35. | |||||
| REF 11 | The 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 12 | Tumour necrosis factor-alpha converting enzyme (TACE) activity in human colonic epithelial cells. Clin Exp Immunol. 2004 Jan;135(1):146-53. | |||||
| REF 13 | Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge. Bioorg Med Chem. 2008 Oct 1;16(19):8781-94. | |||||
| REF 14 | Discovery of beta-benzamido hydroxamic acids as potent, selective, and orally bioavailable TACE inhibitors. Bioorg Med Chem Lett. 2008 Jan 1;18(1):241-6. | |||||
| REF 15 | Chromen-based TNF-alpha converting enzyme (TACE) inhibitors: design, synthesis, and biological evaluation. Bioorg Med Chem. 2008 Jan 1;16(1):530-5. | |||||
| REF 16 | Current perspective of TACE inhibitors: a review. Bioorg Med Chem. 2009 Jan 15;17(2):444-59. | |||||
| REF 17 | Design, 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 18 | Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors. Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63. | |||||
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