Inhibition of MMPs and ADAM/ADAMTS.

Area of Science:

• Biochemistry
• Molecular Biology
• Immunology

Background:

• Matrix metalloproteinases (MMPs), A Disintegrin and Metalloproteinase (ADAM), and ADAM with Thrombospondin Motif (ADAMTS) are zinc-dependent endopeptidases crucial for extracellular matrix degradation and receptor shedding.
• In arthritis, particularly rheumatoid arthritis and osteoarthritis, pro-inflammatory cytokines significantly increase the production of MMPs, ADAMs, and ADAMTS, disrupting joint homeostasis.
• While targeting these enzymes is a therapeutic strategy, direct MMP inhibition has shown limited success in preclinical models of arthritis.

Purpose of the Study:

• To review the role of MMPs, ADAMs, and ADAMTS in arthritis pathogenesis.
• To evaluate the efficacy of current medicinal chemistry strategies targeting these enzymes.
• To highlight the need for novel therapeutic approaches that suppress both the production and activity of MMPs, ADAMs, and ADAMTS.

Main Methods:

• Literature review of studies on MMP, ADAM, and ADAMTS inhibitors in arthritis models.
• Analysis of preclinical and clinical trial data for relevant inhibitors.
• Examination of the impact of pro-inflammatory cytokines on enzyme production in vitro and in vivo.

Main Results:

• Medicinal chemistry strategies directly inhibiting MMPs have largely failed in animal models of arthritis, despite in vitro efficacy in suppressing cytokine-induced production.
• Targeting the 'sheddase' activity of ADAMs, exemplified by the experimental ADAM17 inhibitor GW280264X, is a progressing area.
• An ADAMTS-5 inhibitor (GLPG1972) has advanced to a Phase I clinical trial for osteoarthritis, though many inhibitors fail to progress beyond preclinical stages.

Conclusions:

• Direct inhibition of MMPs has proven largely ineffective in treating arthritis.
• Targeting ADAM and ADAMTS enzymes, particularly their 'sheddase' activity, represents a promising therapeutic avenue.
• Developing novel strategies to suppress both the production and activity of MMPs, ADAMs, and ADAMTS is essential for effective arthritis treatment.