ADAMTS5 | M12: Astacin/Adamalysin | IUPHAR/BPS Guide to PHARMACOLOGY

ADAMTS5

Target id: 1678

Nomenclature: ADAMTS5

Family: M12: Astacin/Adamalysin

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     ADAMTS5 has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 930 21q21.3 ADAMTS5 ADAM metallopeptidase with thrombospondin type 1 motif 5
Mouse - 930 16 C3.3 Adamts5 a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 5 (aggrecanase-2)
Rat - 928 11q11 Adamts5 ADAM metallopeptidase with thrombospondin type 1 motif, 5
Previous and Unofficial Names
ADAMTS11 | ADMP-2 | aggrecanase-2 | ADAM metallopeptidase with thrombospondin type 1 motif | a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif
Database Links
Specialist databases
MEROPS M12.225 (Hs)
Other databases
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 3.4.24.-

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
compound 15c [PMID: 21536437] Hs Inhibition 7.7 pIC50 2
pIC50 7.7 (IC50 2x10-8 M) [2]
Immunopharmacology Comments
ADAMTS4 and -5 diminish cartilage integrity in rheumatoid arthritis (RA), via their participation in aggrecan degradation [4-5]. ADAMTS5 is a validated drug target for osteoarthritis (OA), with experimental inhibitors attenuating joint damage in models of OA. Galapagos NV have an active ADAMTS5 programme, with their lead compound GLPG1972 (licensed to Servier in mid-2017) in Phase 1 clinical trial in patients with OA (see NCT03311009). A humanized anti-ADAMTS5 monoclonal antibody, GSK2394002 [3] which inhibits ADAMTS5 catalytic activity (Ki 0.08 nM), was identified as a potential disease modifying therapeutic for OA, but to date (April 2018) this does not appear to have progressed beyond preclinical evaluation.
Immuno Disease Associations
Disease Name:  Rheumatoid arthritis
Disease Synonyms:  no synonynms
Comment:  ADAMTS5 is involved in RA pathogenesis.
Disease X-refs:  Disease Ontology: DOID:7148
OMIM: 180300
References:  4-5
Disease Name:  Osteoarthritis
Disease Synonyms:  no synonynms
Comment:  Preclinical molecular target for OA. Anti-ADAMTS5-selective monoclonal antibodies CRB0017 and GSK2394002 have indicated some efficacy in OA disease models.
Disease X-refs:  Disease Ontology: DOID:8398
References:  1,3
Disease Name:  Osteoarthritis
Disease Synonyms:  no synonynms
Comment:  ADAMTS4 and -5 are major players in development of OA.
Disease X-refs:  Disease Ontology: DOID:8398
References:  6

References

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1. Chiusaroli R, Visentini M, Galimberti C, Casseler C, Mennuni L, Covaceuszach S, Lanza M, Ugolini G, Caselli G, Rovati LC et al.. (2013) Targeting of ADAMTS5's ancillary domain with the recombinant mAb CRB0017 ameliorates disease progression in a spontaneous murine model of osteoarthritis. Osteoarthr. Cartil., 21 (11): 1807-10. [PMID:23954517]

2. De Savi C, Pape A, Sawyer Y, Milne D, Davies C, Cumming JG, Ting A, Lamont S, Smith PD, Tart J et al.. (2011) Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis. Bioorg. Med. Chem. Lett., 21 (11): 3301-6. [PMID:21536437]

3. Larkin J, Lohr TA, Elefante L, Shearin J, Matico R, Su JL, Xue Y, Liu F, Genell C, Miller RE et al.. (2015) Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification. Osteoarthr. Cartil., 23 (8): 1254-66. [PMID:25800415]

4. McInnes IB, Schett G. (2011) The pathogenesis of rheumatoid arthritis. N. Engl. J. Med., 365 (23): 2205-19. [PMID:22150039]

5. Porter S, Clark IM, Kevorkian L, Edwards DR. (2005) The ADAMTS metalloproteinases. Biochem. J., 386 (Pt 1): 15-27. [PMID:15554875]

6. Song RH, Tortorella MD, Malfait AM, Alston JT, Yang Z, Arner EC, Griggs DW. (2007) Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum., 56 (2): 575-85. [PMID:17265492]

How to cite this page

M12: Astacin/Adamalysin: ADAMTS5. Last modified on 06/04/2018. Accessed on 18/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1678.