Selective Matrix Metalloproteinase Inhibitors for Cancer

Abstract

The matrix metalloproteinases are a family of nearly 30 enzymes that are intimately involved in tissue remodeling. Disease processes associated with the matrix metalloproteinases are generally related to imbalance between the inhibition and activation of matrix metalloproteinases resulting in excessive degradation of the extracellullar matrix. These include osteoarthritis, rheumatoid arthritis, tumor metastasis and congestive heart failure. Despite massive research and development efforts, there are only two drugs launched on the market: periostat (doxycycline), a tetracycline used for periodontal disease and glucosemine sulfate, for osteoarthritis. Possible reasons for the low success rate of matrix metalloproteinase inhibitors in the clinic are mainly from unwanted side effects caused by their lack of selectivity, since inhibition of collagenase-1 may be responsible for the musculoskeletal side effects observed clinically with broad-spectrum inhibitors. Considering these data, many efforts were directed to developing a more selective second generation of inhibitors against the specific matrix metalloproteinases believed to be involved in the different pathologies. This review mainly focuses on selective matrix metalloproteinase inhibitors development on matrix metalloproteinases in terms of antitumor since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, natural products and their derivatives. Through these methods, new hope is emerging in the form of synthetic and natural matrix metalloproteinase inhibitors for the prevention and treatment of cancer.

Examination of Mechanism of N-Acetyl-1-d-myo-inosityl-2-amino-2-deoxy-α-d-glucopyranoside Deacetylase (MshB) Reveals Unexpected Role for Dynamic Tyrosine

“…MshB is an attractive drug target because it catalyzes the rate-limiting step in MSH biosynthesis (11), it is a metalloenzyme (12)(13)(14), and the three-dimensional structure is known (15,16). There are past successes in targeting metalloenzymes, including inhibitors of carbonic anhydrase, matrix metalloproteases, and angiotensin-converting enzyme (17)(18)(19)(20). Because inhibitors of metalloenzymes typically contain a group that binds to the catalytic metal ion, we previously examined the cofactor preferences of MshB and found that MshB is a cambialistic metalloenzyme whose in vitro activity follows the following trend: Fe 2ϩ Ͼ Co 2ϩ Ͼ Zn 2ϩ Ͼ Mn 2ϩ Ͼ Ni 2ϩ (14).…”

The Activity and Cofactor Preferences of N-Acetyl-1-d-myo-inosityl-2-amino-2-deoxy-α-d-glucopyranoside Deacetylase (MshB) Change Depending on Environmental Conditions

“…MshB is an attractive drug target because it is a metalloenzyme; there are past successes in targeting metalloenzymes, including inhibitors of carbonic anhydrase, matrix metalloproteases, and angiotensinconverting enzyme (12)(13)(14)(15). Inhibitors of metalloenzymes typically contain a group that binds to the catalytic metal ion.…”

Carbamoylphosphonates inhibit autotaxin and metastasis formationin vivo

“…Further, inhibition of CAIX has been shown to result in regression or growth inhibition of mouse and human breast tumors as well as inhibition of cancer metastasis formation 25 . MMPs aid tumor progression by increasing cancer cell growth, migration and invasion, angiogenesis and metastasis 26,27 . In recent years, we have reported in a series of papers that show CPOs are able to act both in vitro and in vivo as inhibitors of the extracellular MMP 2 [16][17][18] and possess zinc-binding ability 28 .…”