Challenges in Matrix Metalloproteinases Inhibition

Abstract

Matrix metalloproteinases are enzymes that degrade the extracellular matrix. They have different substrates but similar structural organization. Matrix metalloproteinases are involved in many physiological and pathological processes and there is a need to develop inhibitors for these enzymes in order to modulate the degradation of the extracellular matrix (ECM). There exist two classes of inhibitors: endogenous and synthetics. The development of synthetic inhibitors remains a great challenge due to the low selectivity and specificity, side effects in clinical trials, and instability. An extensive review of currently reported synthetic inhibitors and description of their properties is presented.

Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution

“…Hydantoin-based ADAM17 inhibitors were extensively studied by Merck. In 2010, a promising acetylene-based hydantoin derivative was reported by Girijavallabhan et al (compound 4 , Table 3 ) and was the starting point to explore hydantoin-derived ADAM17 inhibitors with improved bioavailability and better pharmacokinetic profile [ 186 ]. In 2017, Tong et al modified the hydantoin-based structure by replacing the pendant acetylene with an aza benzofuran group.…”

Current Status and Perspectives of Protease Inhibitors and Their Combination with Nanosized Drug Delivery Systems for Targeted Cancer Therapy

“…A group of non-peptidic inhibitors, including MMI270, prinomastat, marimastat and batimastat was designed with a zinc-binding hydroxamate group. 31 Investigations to eliminate the significant limitations of early agents and decrease their side effects, low lability and specificity prompted the development of less toxic and more potent inhibitors. 31 The second generation of non-hydroxamate MMP inhibitors was designed with different peptidomimetic and non-peptidomimetic structures, such as carboxylic acids (tanomastat), thiols (rebimastat) and others.…”

“…31 Investigations to eliminate the significant limitations of early agents and decrease their side effects, low lability and specificity prompted the development of less toxic and more potent inhibitors. 31 The second generation of non-hydroxamate MMP inhibitors was designed with different peptidomimetic and non-peptidomimetic structures, such as carboxylic acids (tanomastat), thiols (rebimastat) and others. 31,32 Although the early inhibitors were improved, both the hydroxamate and nonhydroxamate groups failed to pass the early stages of human clinical trials.…”

“…31 The second generation of non-hydroxamate MMP inhibitors was designed with different peptidomimetic and non-peptidomimetic structures, such as carboxylic acids (tanomastat), thiols (rebimastat) and others. 31,32 Although the early inhibitors were improved, both the hydroxamate and nonhydroxamate groups failed to pass the early stages of human clinical trials. 33 Despite their enhanced inhibitory effects, the broad-spectrum synthetic MMP inhibitors did not meet the relevant criteria when tested in humans.…”

Matrix Metalloproteinases in Health and Disease

“…The paper by Laronha H. [ 13 ] extensively reviewed the currently reported synthetic inhibitors of MMPs and also provided an accurate description of their properties. In particular, Hydroxamate-Based Inhibitors, Non-Hydroxamate-Based Inhibitors, Catalytic Domain (Non-Zinc Binding) Inhibitors, Allosteric and Exosite Inhibitors, and Antibody-Based Inhibitors are presented and discussed.…”