ADAMTS5

Target not currently curated in GtoImmuPdb

Target id: 1678

Nomenclature: ADAMTS5

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 48.34 cM	Adamts5	ADAM metallopeptidase with thrombospondin type 1 motif 5
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

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
Alphafold	Q9UNA0 (Hs), Q9R001 (Mm)
BRENDA	3.4.24.-
CATH/Gene3D	2.20.100.10, 3.40.390.10
ChEMBL Target	CHEMBL2285 (Hs), CHEMBL4879523 (Mm)
Ensembl Gene	ENSG00000154736 (Hs), ENSMUSG00000022894 (Mm), ENSRNOG00000057794 (Rn)
Entrez Gene	11096 (Hs), 23794 (Mm), 304135 (Rn)
Human Protein Atlas	ENSG00000154736 (Hs)
KEGG Enzyme	3.4.24.-
KEGG Gene	hsa:11096 (Hs), mmu:23794 (Mm), rno:304135 (Rn)
OMIM	605007 (Hs)
Pharos	Q9UNA0 (Hs)
RefSeq Nucleotide	NM_007038 (Hs), NM_011782 (Mm), NM_198761 (Rn)
RefSeq Protein	NP_008969 (Hs), NP_035912 (Mm), NP_942056 (Rn)
UniProtKB	Q9UNA0 (Hs), Q9R001 (Mm)
Wikipedia	ADAMTS5 (Hs)

Selected 3D Structures

Image of receptor 3D structure from RCSB PDB

Description:	Crystal Structure of the Catalytic Domain of ADAMTS-5 in Complex with the Inhibitor GLPG1972
PDB Id:	6YJM
Ligand:	aldumastat
Resolution:	2.25Å
Species:	Human
References:	1

Enzyme Reaction

EC Number: 3.4.24.-

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Inhibitors

Key to terms and symbols

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Ligand		Sp.	Action	Value	Parameter	Reference
aldumastat		Hs	Inhibition	7.7	pIC₅₀	1
⤷	pIC₅₀ 7.7 (IC₅₀ 1.9x10^-8 M) [1]
compound 15c [PMID: 21536437]		Hs	Inhibition	7.7	pIC₅₀	3
⤷	pIC₅₀ 7.7 (IC₅₀ 2x10^-8 M) [3]

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:	7

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:	5-6

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:	2,4

General Comments
ADAMTS4 and -5 diminish cartilage integrity in rheumatoid arthritis (RA), via their participation in aggrecan degradation [5-6]. 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 [8], 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 [4] also inhibits ADAMTS5 catalytic activity (K_i 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.

General Comments

ADAMTS4 and -5 diminish cartilage integrity in rheumatoid arthritis (RA), via their participation in aggrecan degradation [5-6]. 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 [8], 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 [4] also inhibits ADAMTS5 catalytic activity (K_i 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. Brebion F, Gosmini R, Deprez P, Varin M, Peixoto C, Alvey L, Jary H, Bienvenu N, Triballeau N, Blanque R et al.. (2021) Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis. J Med Chem, 64 (6): 2937-2952. [PMID:33719441]

2. 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]

3. 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]

4. 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]

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

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

7. 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]

8. 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 26/06/2023. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1678.

ADAMTS5

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