Target Information

Target General Infomation
Target ID
T98896
Former ID
TTDR00697
Target Name
Aggrecanase
Gene Name
ADAMTS5
Synonyms
ADAMTS-5; A disintegrin and metalloproteinase with thrombospondinmotifs 5; ADAM-TS 11; ADAM-TS 5; ADAM-TS5; ADMP-2; Aggrecanase-2; ADAMTS5
Target Type
Clinical Trial
Disease Osteoarthritis [ICD9: 715; ICD10: M15-M19, M47]
Function
Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases. May play a role in proteolytic processing mostly during the peri-implantation period.
BioChemical Class
Peptidase
Target Validation
T98896
UniProt ID
Q9UNA0
EC Number
EC 3.4.24.82
Sequence
MLLGWASLLLCAFRLPLAAVGPAATPAQDKAGQPPTAAAAAQPRRRQGEEVQERAEPPGH
PHPLAQRRRSKGLVQNIDQLYSGGGKVGYLVYAGGRRFLLDLERDGSVGIAGFVPAGGGT
SAPWRHRSHCFYRGTVDGSPRSLAVFDLCGGLDGFFAVKHARYTLKPLLRGPWAEEEKGR
VYGDGSARILHVYTREGFSFEALPPRASCETPASTPEAHEHAPAHSNPSGRAALASQLLD
QSALSPAGGSGPQTWWRRRRRSISRARQVELLLVADASMARLYGRGLQHYLLTLASIANR
LYSHASIENHIRLAVVKVVVLGDKDKSLEVSKNAATTLKNFCKWQHQHNQLGDDHEEHYD
AAILFTREDLCGHHSCDTLGMADVGTICSPERSCAVIEDDGLHAAFTVAHEIGHLLGLSH
DDSKFCEETFGSTEDKRLMSSILTSIDASKPWSKCTSATITEFLDDGHGNCLLDLPRKQI
LGPEELPGQTYDATQQCNLTFGPEYSVCPGMDVCARLWCAVVRQGQMVCLTKKLPAVEGT
PCGKGRICLQGKCVDKTKKKYYSTSSHGNWGSWGSWGQCSRSCGGGVQFAYRHCNNPAPR
NNGRYCTGKRAIYRSCSLMPCPPNGKSFRHEQCEAKNGYQSDAKGVKTFVEWVPKYAGVL
PADVCKLTCRAKGTGYYVVFSPKVTDGTECRLYSNSVCVRGKCVRTGCDGIIGSKLQYDK
CGVCGGDNSSCTKIVGTFNKKSKGYTDVVRIPEGATHIKVRQFKAKDQTRFTAYLALKKK
NGEYLINGKYMISTSETIIDINGTVMNYSGWSHRDDFLHGMGYSATKEILIVQILATDPT
KPLDVRYSFFVPKKSTPKVNSVTSHGSNKVGSHTSQPQWVTGPWLACSRTCDTGWHTRTV
QCQDGNRKLAKGCPLSQRPSAFKQCLLKKC
Structure
2RJP; 3B2Z; 4WK7; 4WKE; 4WKI; 2RJQ; 3B8Z; 3HY7; 3HY9; 3HYG; 3LJT
Drugs and Mode of Action
Drug(s) AGG-523 Drug Info Phase 1 Osteoarthritis [521997]
SC-44463 Drug Info Terminated Discovery agent [546364]
Inhibitor AGG-523 Drug Info [531304]
Aggrecanase-2 inhibitors Drug Info [543458]
compound 15c Drug Info [531458]
CR-5259 Drug Info [543457]
SC-44463 Drug Info [526154]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
Reactome Degradation of the extracellular matrix
O-glycosylation of TSR domain-containing proteins
WikiPathways Endochondral Ossification
Vitamin D Receptor Pathway
References
Ref 521997ClinicalTrials.gov (NCT00454298) Study Evaluating AGG-523 in Subjects With Severe Osteoarthritis Requiring Total Knee Replacement. U.S. National Institutes of Health.
Ref 546364Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007717)
Ref 526154J Med Chem. 2001 Oct 11;44(21):3347-50.Design and synthesis of a series of (2R)-N(4)-hydroxy-2-(3-hydroxybenzyl)-N(1)- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide derivatives as potent, selective, and orally bioavailable aggrecanase inhibitors.
Ref 531304Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor. Osteoarthritis Cartilage. 2011 Mar;19(3):315-23.
Ref 531458Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis. Bioorg Med Chem Lett. 2011 Jun 1;21(11):3301-6.
Ref 543457(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: 1677).
Ref 543458(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: 1678).

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