Matrix metalloproteinase-3 (MMP-3) plays an important role in the pathology of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). MMP-3 contains a signal peptide, a pro-domain, a catalytic domain, a hinge domain, and a hemopexin domain. Besides, the signal peptide is cleaved off during the secretion process and pro-domain is cleaved during the activation process. Moreover, the catalytic domain has a conserved zinc-binding site. In addition, MMP-3 can activate other MMPs, such as pro-MMP-1, pro-MMP-8, pro-MMP-9, and pro-MMP-13. And hence MMP-3 is an important pathological mediator of ankylosing spondylitis and rheumatoid arthritis. Furthermore, serum MMP-3 levels at baseline were predictive of radiographic progression in an RA cohort. In AS, MMP-3 was a predictor of structural progression. Collectively, the line of data underscores the pathological relevance of MMP-3 in arthritic diseases. UK 356618 is a potent and selective inhibitor of MMP-3 with anti-inflammatory and anti-cancer activity.
UK 356618 is a potent and selective inhibitor of matrix metalloprotease-3 (MMP-3) with an IC50 of 5.9 nM. Besides, UK 356618 is >140-fold less potent against MMP-1, MMP-2, MMP-9, and MMP-14 compared with MMP-3. Nonetheless, inhibition of MMP-3 and selectivity over MMP-2 was remarkably sensitive to the size of the substituent. And it is clearly optimized for a methyl group. Meanwhile, UK 356618 was more widely against other MMPs. Specifically, UK 356618 may be a useful tool for elucidating the contribution of MMP-3 to pathological conditions in which selectivity may be required over other MMPs. In addition, UK 356618 with intravenous injection and 15 mg/kg for 24 h or 7 days of reperfusion significantly reduces MMP3 activity in the brain. All in all, UK 356618 is a potent and selective inhibitor of MMP-3 with anti-inflammatory and anti-cancer activity.