ReviewMMPs as therapeutic targets—Still a viable option?
Introduction
As we have seen from accompanying papers, there is considerable evidence implicating MMP activity in various pathologies including cancer, diseases of the central nervous system (CNS) and disorders of the immune system. Given the many physiological processes that are controlled by MMP activity, it is unsurprising that aberrant proteolysis is a significant problem in multiple disease settings. Studies using relevant disease models in MMP-deficient animals have demonstrated the contribution of MMPs to disease processes. These studies have, however, revealed some surprising, apparently protective functions of various MMP family members. Hence broad-scale MMP inhibition can have both advantageous and problematic consequences. Here we will examine some of these as well as the settings in which inhibiting MMPs can be a successful therapeutic approach. As many readers will be aware, pharmacological MMP inhibitors (MMPIs) have failed in multiple clinical trials [1], [2]. However, we believe that these failures should not define the field and will suggest ways in which future iterations of MMPIs could potentially be of significant therapeutic benefit.
Section snippets
Evidence for targeting MMPs
Proteolysis is a very effective mechanism for introducing diversity into the protein complement of an organism. Unlike many other modifications, however, this is an irreversible change. For this reason, although proteases are a major group within the proteome [3], activity levels of proteases such as MMPs are tightly controlled [4]. This is logical since rampant proteolysis would not be an efficient way to maintain homeostasis. In disease settings, however, the expression levels of individual
Animal models
Expression analyses provide evidence that a protein target is present at high levels when a disease is manifest and, ideally, absent in the healthy state. However, these types of studies cannot determine whether the presence of the particular protein is in any way associated with the disease process or whether it is merely an ancillary event. Using animal models in which expression can be manipulated provides some evidence for the contributory effect of the particular protein to the disease
Limitations of animal models
Although studies in MMP-deficient animals are highly suggestive of roles for MMPs in various disease processes, there are some caveats to be aware of. Firstly, as previously noted, most of the MMP-null animals are constitutively null. Hence some of the apparent effects of deficiency apparent in pathological situations may be reflective of an altered physiology that developed as a way to circumvent the MMP deficiency, thus the differing effect seen in the null animal is not actually due to the
Are there situations where MMPs should not be targeted?
When the idea of pharmacological agents that would inhibit MMP function was first suggested, there was a basic assumption that MMPs contributed detrimental activities. Therefore inhibition would be favorable. A significant finding from multiple mouse studies is that MMPs can also be beneficial. This of course should not be surprising as it would not be evolutionarily favorable for development of an entire family of proteases that are only detrimental to an organism! Rather than categorizing
Reasons for non-efficacy of early MMPIs
One of the biggest questions regarding the original MMP inhibitor clinical trials was how they could fail to show any efficacy despite data from multiple animal models suggesting they would be useful [1], [2]. Of course there are always the problems of extrapolating models to the human disease setting. As discussed previously, the animal models are usually concerned with specific disease processes rather than the overwhelming sum of processes that can be present in a human patient.
Conclusion
Overwhelming evidence from animal models strongly suggests a number of therapeutic areas that would benefit from MMP inhibition. These include various cancers, cardiac remodeling post infarction, chronic obstructive pulmonary diseases, cerebral ischemia, multiple sclerosis and certain skin and eye diseases [108]. The latter two settings have the advantage of allowing local, non-systemic delivery thus potentially avoiding the MSS side effects that have plagued clinical trials of orally dosed
Acknowledgements
The author would like to acknowledge the Susan G. Komen Foundation (BCTR0600431) for funding. Apologies to the many authors whose work could not be mentioned due to space limitations.
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2021, European Journal of Medicinal ChemistryCitation Excerpt :It had been observed that cipemastat/Ro32-3555 or trocade (Fig. 5; 12), a MMP-1, -8, and -13 selective hydroxamate based MMPI, developed by Roche, did not report any MSS related toxicities in clinical trials, designed with healthy male volunteers and later with rheumatoid arthritis patients [208,209]. Another hypothesis resulting MSS related toxicities in patients treated with early non-selective MMPIs like marimastat (2) and batimastat (1) were inhibitions of ADAM-10 and ADAM-17 [11,210,211]. The correlation of MMP-1 and MSS was also contradictory because Ro32-3555 (12) was a MMP-1, MMP-8, and MMP-13 (Ki = 3.0 nM, 4.4 nM and 3.4 nM) selective hydroxamate based MMPI over MMP-2, MMP-3, and MMP-9 (Ki = 154 nM, 527 nM and 59 nM) did not reported any MSS related toxicities in clinical trials (CTs), designed with healthy male volunteers and later with rheumatoid arthritis patients [208,209,212].
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