ADAM17

Immunopharmacology Ligand Target has curated data in GtoImmuPdb

Target id: 1662

Nomenclature: ADAM17

Gene and Protein Information
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
CD156B \| cSVP \| snake venom-like protease \| TACE \| TNF α convertase \| TNF α-converting enzyme \| tumor necrosis factor, alpha, converting enzyme

Database Links
Specialist databases
MEROPS	M12.217 (Hs)
Other databases
Alphafold	P78536 (Hs), Q9Z0F8 (Mm), Q9Z1K9 (Rn)
BRENDA	3.4.24.86
CATH/Gene3D	3.40.390.10, 4.10.70.10
ChEMBL Target	CHEMBL3706 (Hs), CHEMBL4379 (Mm), CHEMBL2523 (Rn)
Ensembl Gene	ENSG00000151694 (Hs), ENSMUSG00000052593 (Mm), ENSRNOG00000060694 (Rn)
Entrez Gene	6868 (Hs), 11491 (Mm), 57027 (Rn)
Human Protein Atlas	ENSG00000151694 (Hs)
KEGG Enzyme	3.4.24.86
KEGG Gene	hsa:6868 (Hs), mmu:11491 (Mm), rno:57027 (Rn)
OMIM	603639 (Hs)
Orphanet	ORPHA299456 (Hs)
Pharos	P78536 (Hs)
RefSeq Nucleotide	NM_003183 (Hs), NM_001277266 (Mm), NM_009615 (Mm), NM_020306 (Rn)
RefSeq Protein	NP_003174 (Hs), NP_001264195 (Mm), NP_033745 (Mm), NP_064702 (Rn)
SynPHARM	82602 (in complex with IK-862)
UniProtKB	P78536 (Hs), Q9Z0F8 (Mm), Q9Z1K9 (Rn)
Wikipedia	ADAM17 (Hs)

Selected 3D Structures

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

EC Number: 3.4.24.86

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Inhibitors

Key to terms and symbols

View all chemical structures

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Ligand		Sp.	Action	Value	Parameter	Reference
IK-862		Hs	Inhibition	9.3	pK_i	3
⤷	pK_i 9.3 (K_i 5.6x10^-10 M) [3]
SL422		Pig	Inhibition	7.9	pK_i	14
⤷	pK_i 7.9 (K_i 1.2x10^-8 M) [14] Description: Partially purified enzyme from pancreas.
BMS-561392		Hs	Inhibition	8.7	pIC₅₀	2
⤷	pIC₅₀ 8.7 (IC₅₀ 2x10^-9 M) [2]
ilomastat		Hs	Inhibition	8.1	pIC₅₀	10
⤷	pIC₅₀ 8.1 (IC₅₀ 7.5x10^-9 M) [10] Description: Measured in an in vitro assay.
apratastat		Hs	Inhibition	7.7	pIC₅₀	6
⤷	pIC₅₀ 7.7 (IC₅₀ 2x10^-8 M) [6]
GI254023X		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 K_d of 0.039 nM and inhibits its catalytic activity with a K_i 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.

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:

Immuno Process:

Immuno Process:

Immuno Process:

Immuno Process:

Immune system development

Immuno Process:

Cytokine production & signalling

Immuno Process:

Chemotaxis & migration

Immuno Process:

Cellular signalling

Clinically-Relevant Mutations and Pathophysiology

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.

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.

References

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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]