MATRIX METALLOPROTEINASE INHIBITORS WITH ANTICANCER ACTIVITY

Abstract

Objective: To provide up-to-date information on the structure, function, and specific activities of matrix metalloproteinases (MMPs), with particular emphasis on gelatinases MMP-2 and MMP-9 as anticancer therapeutic targets due to their roles in cancer development, angiogenesis, tumor invasion, and metastasis. Additionally, this review evaluates the design, development, and selectivity strategies of gelatinase inhibitors, focusing primarily on synthetic MMP inhibitors.Result and Discussion: MMPs are enzymes belonging to the metalloproteinase family that participate in numerous physiological and pathological processes, including tissue remodeling, wound healing, and angiogenesis, by degrading structural components of the extracellular matrix. The overexpression of gelatinases MMP-2 and MMP-9 in various malignancies has rendered these enzymes significant therapeutic targets. First-generation MMP inhibitors consisted of compounds bearing zinc-binding groups (ZBGs), such as hydroxamic acid, thiol, carboxylate, phosphonate, or nitrogen-containing heterocyclic structures. Hydroxamate-based inhibitors emerged as prominent candidates in early studies due to their strong zinc-chelating properties and broad-spectrum activity; however, clinical limitations, including lack of selectivity and musculoskeletal toxicity, have driven the development of alternative approaches, such as ZBG-free inhibitors and mechanism-based or allosteric inhibition strategies. Structural studies have revealed the critical role of the S1′ subsite in determining selectivity, thereby guiding the rational design of narrow-spectrum, gelatinase-selective inhibitors. Furthermore, protein engineering approaches, antibody-based inhibitors, and biological agents such as TIMPs and pro-domain-like molecules represent next-generation strategies that enhance selectivity and biocompatibility.