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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 1662

Nomenclature: ADAM17

Family: M12: Astacin/Adamalysin

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 824 2p25.1 ADAM17 ADAM metallopeptidase domain 17
Mouse 1 827 12 8.3 cM Adam17 a disintegrin and metallopeptidase domain 17
Rat 1 827 6q16 Adam17 ADAM metallopeptidase domain 17
Previous and Unofficial Names Click here for help
CD156B | cSVP | snake venom-like protease | TACE | TNF α convertase | TNF α-converting enzyme | tumor necrosis factor, alpha, converting enzyme
Database Links Click here for help
Specialist databases
MEROPS M12.217 (Hs)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
RefSeq Nucleotide
RefSeq Protein
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of TACE in complex with IK682.
PDB Id:  2fv5
Ligand:  IK-862
Resolution:  2.1Å
Species:  Human
References:  8
Enzyme Reaction Click here for help
EC Number:

Download all structure-activity data for this target as a CSV file go icon to follow link

Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
IK-862 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.3 pKi 3
pKi 9.3 (Ki 5.6x10-10 M) [3]
SL422 Small molecule or natural product Pig Inhibition 7.9 pKi 14
pKi 7.9 (Ki 1.2x10-8 M) [14]
Description: Partially purified enzyme from pancreas.
BMS-561392 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.7 pIC50 2
pIC50 8.7 (IC50 2x10-9 M) [2]
ilomastat Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 10
pIC50 8.1 (IC50 7.5x10-9 M) [10]
Description: Measured in an in vitro assay.
apratastat Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.7 pIC50 6
pIC50 7.7 (IC50 2x10-8 M) [6]
GI254023X Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 3.3 pIC50 5
pIC50 3.3 (IC50 5.41x10-4 M) [5]
View species-specific inhibitor tables
Antibody Comments
An anti-ADAM17 (TACE; TNFα converting enzyme) monoclonal antibody, MEDI3622 [11], has shown anti-proliferative activity in tumour models (IC50 ~26 nM vs. H292 cells) [12]. MEDI3622 binds ADAM17 with a Kd of 0.039 nM and inhibits its catalytic activity with a Ki of 3.1 nM [12].
Immunopharmacology Comments
The proteolytic activity of ADAM17 (a type I transmembrane metalloproteinase; a.k.a.TNF-alpha converting enzyme or TACE) is involved in the shedding of the extracellular domains of several transmembrane proteins e.g. cytokines (TNFα), growth factors, receptors (IL-6R and TNF-R for example) and adhesion molecules. Cleavage of substrates, including TNFα, IL-6R and L-selectin, produce pro-inflammatory effects stimulating both innate and acquired immune responses. ADAM17 activity is crucial during development (ADAM17 knockout is embryonic lethal), and it has been shown that the soluble IL-6R/IL-6 complex generates agonist-like signals in a process termed IL-6 trans-signaling. The generation and maintenance of several inflammatory and autoimmune diseases is driven by IL-6 trans-signaling [1]. ADAM17 activity may also be involved in directing migration of activated lymphocytes and neutrophils in vivo, by catalysing the shedding of L-selectin from the surface of leukocytes. ADAM17 is being investigated as a novel therapeutic target in immune-related diseases such as rheumatoid arthritis (RA) [7], but also plays roles in tissue regeneration and cancer development.
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Inflammatory skin and bowel disease, neonatal, 1; NISBD1
Synonyms: Neonatal inflammatory skin and bowel disease [Orphanet: ORPHA294023]
OMIM: 614328
Orphanet: ORPHA294023
General Comments
There is evidence that ADAM17 cleaves angiotensin converting enzyme 2 (ACE2), leading to shedding of the ACE2 ectodmain as a soluble entity [4,9]. Given that ACE2 is the principal binding site for SARS-CoV-2 [13], it could be forseen that exploiting ADAM17's ACE2-sheddase activity (for example using a pharmacological activator, increasing its phosphorylation by upstream mediators, or otherwise upregulating its expression) could lead to release of ACE2/coronavirus complexes, as a mechanism to reduce the ability of the virus to infect lung epithelial cells. The obvious caveat to this approach would be to consider the effect that reducing membrane ACE2 could have on the renin-angiotensin system and other biological processes.


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1. Chalaris A, Garbers C, Rabe B, Rose-John S, Scheller J. (2011) The soluble Interleukin 6 receptor: generation and role in inflammation and cancer. Eur J Cell Biol, 90 (6-7): 484-94. [PMID:21145125]

2. DasGupta S, Murumkar PR, Giridhar R, Yadav MR. (2009) Current perspective of TACE inhibitors: a review. Bioorg Med Chem, 17 (2): 444-59. [PMID:19095454]

3. Georgiadis D, Yiotakis A. (2008) Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge. Bioorg Med Chem, 16 (19): 8781-94. [PMID:18790648]

4. Grobe N, Di Fulvio M, Kashkari N, Chodavarapu H, Somineni HK, Singh R, Elased KM. (2015) Functional and molecular evidence for expression of the renin angiotensin system and ADAM17-mediated ACE2 shedding in COS7 cells. Am J Physiol, Cell Physiol, 308 (9): C767-77. [PMID:25740155]

5. Hoettecke N, Ludwig A, Foro S, Schmidt B. (2010) Improved synthesis of ADAM10 inhibitor GI254023X. Neurodegener Dis, 7 (4): 232-8. [PMID:20197648]

6. Levin JI, Chen JM, Laakso LM, Du M, Schmid J, Xu W, Cummons T, Xu J, Jin G, Barone D et al.. (2006) Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates. Bioorg Med Chem Lett, 16 (6): 1605-9. [PMID:16426848]

7. Moss ML, Sklair-Tavron L, Nudelman R. (2008) Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheumatol, 4 (6): 300-9. [PMID:18414459]

8. Niu X, Umland S, Ingram R, Beyer BM, Liu YH, Sun J, Lundell D, Orth P. (2006) IK682, a tight binding inhibitor of TACE. Arch Biochem Biophys, 451 (1): 43-50. [PMID:16762314]

9. Oarhe CI, Dang V, Dang M, Nguyen H, Gopallawa I, Gewolb IH, Uhal BD. (2015) Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts. Pediatr Res, 77 (5): 656-62. [PMID:25665060]

10. Oh M, Im I, Lee YJ, Kim YH, Yoon JH, Park HG, Higashiyama S, Kim YC, Park WJ. (2004) Structure-based virtual screening and biological evaluation of potent and selective ADAM12 inhibitors. Bioorg Med Chem Lett, 14 (24): 6071-4. [PMID:15546732]

11. Peng L, Cook K, Xu L, Cheng L, Damschroder M, Gao C, Wu H, Dall'Acqua WF. (2016) Molecular basis for the mechanism of action of an anti-TACE antibody. MAbs, 8 (8): 1598-1605. [PMID:27610476]

12. Rios-Doria J, Sabol D, Chesebrough J, Stewart D, Xu L, Tammali R, Cheng L, Du Q, Schifferli K, Rothstein R et al.. (2015) A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non-EGFR-Mediated Pathways. Mol Cancer Ther, 14 (7): 1637-49. [PMID:25948294]

13. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. (2020) Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell, 181 (2): 281-292.e6. [PMID:32155444]

14. Xue CB, Voss ME, Nelson DJ, Duan JJ, Cherney RJ, Jacobson IC, He X, Roderick J, Chen L, Corbett RL et al.. (2001) 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, 44 (16): 2636-60. [PMID:11472217]

How to cite this page

M12: Astacin/Adamalysin: ADAM17. Last modified on 31/03/2020. Accessed on 24/07/2024. IUPHAR/BPS Guide to PHARMACOLOGY,