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ADAMTS5

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Target not currently curated in GtoImmuPdb

Target id: 1678

Nomenclature: ADAMTS5

Family: M12: Astacin/Adamalysin

Gene and Protein Information Click here for help
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 48.34 cM 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 Click here for help
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 Click here for help
Specialist databases
MEROPS M12.225 (Hs)
Other databases
Alphafold
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction Click here for help
EC Number: 3.4.24.-

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

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 15c [PMID: 21536437] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.7 pIC50 2
pIC50 7.7 (IC50 2x10-8 M) [2]
Immuno Disease Associations
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
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
General 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 agent GLPG1972/S201086 a small molecule ADAMTS5 inhibitor [7], licensed to Servier in mid-2017) having completed Phase 2 clinical trial in patients with knee OA (see NCT03595618). Unpublished data released in October 2020, indicated that GLPG1972 failed to improve outcomes in these patients. GSK's humanized anti-ADAMTS5 monoclonal antibody, GSK2394002 [3] also inhibits ADAMTS5 catalytic activity (Ki 0.08 nM), and was proposed as a potential disease modifying therapeutic for OA, but as of August 2020 it does not appear to have progressed beyond preclinical evaluation.

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]

7. van der Aar EM, Desrivot J, Fagard L, Amantini D, Larsson S, Struglics A, Lohmander S, Vanhoutte F, Dupont S. Abstract 584: ADAMTS-5 inhibitor GLPG1972, a potential new treatment in osteoarthritis, shows favorable safety, pharmacokinetics and pharmacodynamics in healthy subjects. Accessed on 19/10/2020. Modified on 19/10/2020. oarsijournal.com, https://www.oarsijournal.com/article/S1063-4584(18)30723-4/abstract. DOI: 10.1016/j.joca.2018.02.623

How to cite this page

M12: Astacin/Adamalysin: ADAMTS5. Last modified on 19/10/2020. Accessed on 29/01/2022. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1678.