Classical MMP inhibitors

Considering the pivotal roles of matrix metalloproteinases (MMPs) in tumor progression, MMP inhibitors (MMPIs) have emerged as promising therapeutic agents, resulting in the development of several generations of inhibitors and candidate cancer drugs. First-generation inhibitors were conceived as peptide-based inhibitors and hydroxamate-based peptidomimetics such as batimastat and marimastat, demonstrating at preclinical level the strong anticancer activity by targeting the catalytic Zn²⁺ ion of MMPs. Nevertheless, their clinical success was limited by poor bioavailability and selectivity, resulting to severe side-effects. Second-generation MMPIs consisted of alternative zinc-binding groups, such as thiol, carboxylic acid, pyrimidine, and hydroxypyrone moieties compounds, resulting in failure in clinical trials of improved candidate drugs such as prinomastat and tanomastat due to low oral bioavailability and safety concerns. A major issue has been the non-specific inhibition across multiple MMP family members due to high conservation of the MMP catalytic site. Herein is summarized the development of MMP inhibitors and are described those compounds that reached clinical trials. It is expected that advances in structural biology highlighting the structural differences among MMPs may facilitate the development of more selective inhibitors with improved efficacy and reduced toxicity and enable new MMPI as candidate cancer drugs.