Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Abstract

Matrix metalloproteinases (MMPs) are involved in a multitude of severe diseases. Despite MMPs being considered druggable targets, past drug‐discovery programs have not delivered the anticipated clinical benefits. This review examines the latest structural evolution of small‐molecule inhibitors of MMPs, with a focus on the development of novel chemical entities with improved affinity and selectivity profiles. X‐ray crystallographic data of the protein targets and cocrystal structures with inhibitors proved to be key for the success achieved during this ambitious endeavor. An evolutionary view on the structural diversity generated for this class of molecules is provided. This encouraging development paves the way for the clinical utilization of this class of highly relevant therapeutic targets. The structure‐based design of superior MMP inhibitors highlights the power of this technique and displays strategies for the development of treatment options based on the modulation of challenging drug targets.

Discovery of a Class of Potent and Selective Non‐competitive Sentrin‐Specific Protease 1 Inhibitors

“…SENP1 modulates the activity of several transcription factors, including HADC1 and HIFα, and signaling pathways such as the androgen‐dependent (AR) transcription . Through the HIF1α signaling pathway, SENP1 regulates the expression of matrix metalloproteinase 2 (MMP2) and MMP9, two critical remodeling proteins involved in the progression of cancer . Despite the strong evidence given, only a very limited number of SENP1 inhibitors is known to date.…”

Matrix Metalloproteinases: How Much Can They Do?

“…Thus, it turned out that MMPs are necessary for multiple and diverse physiological processes, such as reproduction, morphogenesis, embryonic development, bone remodeling, angiogenesis, and tissue repair, but they can also contribute to tissue destruction during cancer development and spreading and in arthritis/osteoarthritis and fibrotic diseases. The association of pathologies with MMP overexpression was also the impetus for the intense exploration of synthetic MMP inhibitors (MMPIs), especially those targeting cancer diseases, in the mid and late 1990s [8,9]. The results of randomized controlled trials were overwhelmingly disappointing for small-molecule MMPIs, due to their poor oral bioavailability, lack of efficacy, dose-limiting toxicities, Int.…”

“…and undesired musculoskeletal side effects [10]. These first-generation synthetic MMPIs targeted broadly by mimicking MMPs' natural substrate (usually collagen) [8], but later innumerable substrates were identified [11]. Unfortunately, these early MMPIs also inactivate proteinases unrelated to the disease but necessary for one or more physiological processes [8]; the importance of ADAMs and ADAMTSs was unknown at the time.…”

“…These first-generation synthetic MMPIs targeted broadly by mimicking MMPs' natural substrate (usually collagen) [8], but later innumerable substrates were identified [11]. Unfortunately, these early MMPIs also inactivate proteinases unrelated to the disease but necessary for one or more physiological processes [8]; the importance of ADAMs and ADAMTSs was unknown at the time. Today, there is consensus that MMPs, ADAMs, and ADAMTSs function in many cell-signaling pathways, in which they are probably even more important than in ECM remodeling [11,12].…”

“…Today, there is consensus that MMPs, ADAMs, and ADAMTSs function in many cell-signaling pathways, in which they are probably even more important than in ECM remodeling [11,12]. In parallel with our increased understanding of the diverse biological roles of these proteinases, the current goal is the development of highly selective inhibitors [8,13] although there is still no approved MMPI available. The only exception is low-dose oral doxycycline (Periostat ® ), which was approved in 1998 as an adjunct for the treatment of adult periodontitis.…”