Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT6AZXG)

• DTT Name: TNF alpha converting enzyme (ADAM17)
• 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
• Gene Name: ADAM17
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: ADA17_HUMAN
• TTD ID: T82393
• EC Number: EC 3.4.24.86
• Sequence:
  MRQSLLFLTSVVPFVLAPRPPDDPGFGPHQRLEKLDSLLSDYDILSLSNIQQHSVRKRDL
  QTSTHVETLLTFSALKRHFKLYLTSSTERFSQNFKVVVVDGKNESEYTVKWQDFFTGHVV
  GEPDSRVLAHIRDDDVIIRINTDGAEYNIEPLWRFVNDTKDKRMLVYKSEDIKNVSRLQS
  PKVCGYLKVDNEELLPKGLVDREPPEELVHRVKRRADPDPMKNTCKLLVVADHRFYRYMG
  RGEESTTTNYLIELIDRVDDIYRNTSWDNAGFKGYGIQIEQIRILKSPQEVKPGEKHYNM
  AKSYPNEEKDAWDVKMLLEQFSFDIAEEASKVCLAHLFTYQDFDMGTLGLAYVGSPRANS
  HGGVCPKAYYSPVGKKNIYLNSGLTSTKNYGKTILTKEADLVTTHELGHNFGAEHDPDGL
  AECAPNEDQGGKYVMYPIAVSGDHENNKMFSNCSKQSIYKTIESKAQECFQERSNKVCGN
  SRVDEGEECDPGIMYLNNDTCCNSDCTLKEGVQCSDRNSPCCKNCQFETAQKKCQEAINA
  TCKGVSYCTGNSSECPPPGNAEDDTVCLDLGKCKDGKCIPFCEREQQLESCACNETDNSC
  KVCCRDLSGRCVPYVDAEQKNLFLRKGKPCTVGFCDMNGKCEKRVQDVIERFWDFIDQLS
  INTFGKFLADNIVGSVLVFSLIFWIPFSILVHCVDKKLDKQYESLSLFHPSNVEMLSSMD
  SASVRIIKPFPAPQTPGRLQPAPVIPSAPAAPKLDHQRMDTIQEDPSTDSHMDEDGFEKD
  PFPNSSTAAKSFEDLTDHPVTRSEKAASFKLQRQNRVDSKETEC
• 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.
• KEGG Pathway:
  Notch signaling pathway (hsa04330)
  Alzheimer's disease (hsa05010)
  Epithelial cell signaling in Helicobacter pylori infection (hsa05120)
• Reactome Pathway:
  Collagen degradation (R-HSA-1442490)
  Regulated proteolysis of p75NTR (R-HSA-193692)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 t(7 (R-HSA-2660826)
  Constitutive Signaling by NOTCH1 HD Domain Mutants (R-HSA-2691232)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  TNF signaling (R-HSA-75893)
  Growth hormone receptor signaling (R-HSA-982772)
  M1580_K2555) Translocation Mutant (9)(NOTCH1)
  Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Apratastat	DM8W4N9	Rheumatoid arthritis	FA20	Phase 2	[1]
Aderbasib	DMYOMSC	Breast cancer	2C60-2C65	Phase 1/2	[2]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GW-3333	DM3PMAZ	Chronic obstructive pulmonary disease	CA22	Preclinical	[3]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
DPC-333	DM4JBQD	Inflammatory bowel disease	DD72	Terminated	[3]

13 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(4-bromophenylsulfonamido)-N-hydroxyacetamide	DMY5STK	Discovery agent	N.A.	Investigative	[4]
2-(biphenyl-4-ylsulfonamido)-N-hydroxyacetamide	DM3PWK7	Discovery agent	N.A.	Investigative	[4]
Batimistat	DMTQX1G	Discovery agent	N.A.	Investigative	[5]
CH4474	DMP9UHT	Discovery agent	N.A.	Investigative	[6]
IK-862	DMJA4UE	Discovery agent	N.A.	Investigative	[7]
IM-491	DMUQO86	Discovery agent	N.A.	Investigative	[8]
N-hydroxy-2-(4-methoxyphenylsulfonamido)acetamide	DM50NKS	Discovery agent	N.A.	Investigative	[4]
N-hydroxy-3-(2-oxo-2H-chromen-3-yl)propanamide	DMWXUCT	Discovery agent	N.A.	Investigative	[9]
N-hydroxy-3-(6-methoxy-2-oxo-2H-chromen-3-yl)	DMA6EPH	Discovery agent	N.A.	Investigative	[9]
PKF-241-466	DM04C9V	Discovery agent	N.A.	Investigative	[10]
PKF-242-484	DMNDLAS	Discovery agent	N.A.	Investigative	[10]
SL422	DM3I2US	Discovery agent	N.A.	Investigative	[11]
SR-973	DMU48OD	Discovery agent	N.A.	Investigative	[12]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Breast cancer	2C82	Breast tissue	3.03E-08	0.15	0.45
Chronic obstructive pulmonary disease	CA23	Lung tissue	4.26E-01	0.06	0.23
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	1.29E-01	0.1	0.37
Rheumatoid arthritis	FA20	Synovial tissue	2.02E-01	0.09	0.23

References

• [1] Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates. Bioorg Med Chem Lett. 2006 Mar 15;16(6):1605-9.
• [2] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [3] Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
• [4] 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.
• [5] 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.
• [6] Tumour necrosis factor-alpha converting enzyme (TACE) activity in human colonic epithelial cells. Clin Exp Immunol. 2004 Jan;135(1):146-53.
• [7] 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.
• [8] 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.
• [9] Chromen-based TNF-alpha converting enzyme (TACE) inhibitors: design, synthesis, and biological evaluation. Bioorg Med Chem. 2008 Jan 1;16(1):530-5.
• [10] Current perspective of TACE inhibitors: a review. Bioorg Med Chem. 2009 Jan 15;17(2):444-59.
• [11] 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.
• [12] Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors. Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63.