TABLE 2.

Potential drugs targeting ADAMTS5 in OA therapy.

Drug type	Drug name	Mechanism	Status	Reference
Monoclonal antibodies	CRB0017	CRB0017 binds to the spacer domain of ADAMTS5 and reduce its proteolytic activity	Preclinical	Chiusaroli et al. (2013)
	GSK2394002	GSK2394002 binds to catalytic/disintegrin-like domains	Preclinical	Larkin et al. (2015)
	2D3, 2D11, 2D5, and 2B9	2D3 and 2D11 react with epitopes in the catalytic/disintegrin-like domains of ADAMTS5	Discovery	Santamaria et al. (2015)
		2D5 binds to thrombospondin type 1 motif and 2B9 binds to the spacer domain
	M6495	M6495 binds to the catalytic and/or disintegrin-like domain	Clinical (phase 1)	AS Siebuhr et al. (2020)
	Sheddase antibodies	Monoclonal antibodies selectively inhibit the LRP-1 sheddases to promote the endocytosis of ADAMTS5	Preclinical	Yamamoto et al. (2017)
	Syndecan 4 specific antibody	Injection of syndecan 4 specific antibody blockes ADAMTS5 protein maturation	Preclinical	Echtermeyer et al. (2009)
Small molecule inhibitors	AGG-523	A reversible, non-hydroxamate, zinc-binding selective inhibitor to both ADAMTS5 and ADAMTS4 developed by Wyeth/Pfizer	Discontinued (phase 1)	Chockalingam et al. (2011)
	Compounda	A series of compounds with carboxylate zinc-binding group	Discovery	Shiozaki et al. (2011)
	Compound 15f, 13g, 13eb	A series of nonclassical zinc-binding group compounds selected via encoded library technology	Discovery	Deng et al. (2012)
	Compound 7	A compound with zinc-binding group moieties in hydantoin series	Preclinical	Durham et al. (2017)
	GLPG1972	A compound with zinc-binding group moieties in hydantoin series	Clinical (phase 2)	Brebion et al. (2021)
	Glycoconjugated arylsulfonamide	A compound with positively charged residue-binding ability to the disintegrin-like domain of ADAMTS5	Discovery	Santamaria et al. (2021)
RNAs	ADAMTS5 siRNA	ADAMTS5 siRNA silences ADAMTS5 gene by interfering with its mRNA translation	Preclinical	Chu et al. (2013)
				Hoshi et al. (2017)
	miRNA-140	miRNA-140 is located in one intron of WWP2 gene and is a regulator of cartilage homeostasis	Preclinical	Si et al. (2017)
	WWP2 mRNA	WWP2 mRNA suppresses ADAMTS5 upstream Runx2 signaling	Preclinical	Mokuda et al. (2019)
	ROR2 siRNA	ROR2 siRNA suppresses ADAMTS5 upstream YAP/TAZ signaling	Preclinical	Thorup et al. (2020)
	Antisense oligonucleotides	Antisense oligonucleotides silences ADAMTS5 gene by interfering with its mRNA translation	Preclinical	Garcia et al. (2019)

^a(1S,2R, 3R)-2,3-Dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates.

^bThe core structure of these compounds is triazine pyrrolidine (4-n-propanephenyl)sulfonamide.