Department of Chemistry & Biochemistry, Florida Atlantic University, Jupiter, FL, USA.
Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, Fort Lauderdale, FL, USA.
Proteomics. 2017 Dec;17(23-24). doi: 10.1002/pmic.201600389. Epub 2017 Sep 15.
Remodeling of the extracellular matrix (ECM) is crucial in development and homeostasis, but also has a significant role in disease progression. Two metalloproteinase families, the matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs), participate in the remodeling of the ECM, either directly or through the liberation of growth factors and cell surface receptors. The correlation of MMP and ADAM activity to a variety of diseases has instigated numerous drug development programs. However, broad-based and Zn -chelating MMP and ADAM inhibitors have fared poorly in the clinic. Selective MMP and ADAM inhibitors have been described recently based on (a) antibodies or antibody fragments or (b) small molecules designed to take advantage of protease secondary binding sites (exosites) or allosteric sites. Clinical trials have been undertaken with several of these inhibitors, while others are in advanced pre-clinical stages.
细胞外基质 (ECM) 的重塑对于发育和体内平衡至关重要，但在疾病进展中也起着重要作用。两种金属蛋白酶家族，基质金属蛋白酶 (MMPs) 和解整合素金属蛋白酶 (ADAMs)，通过直接或通过释放生长因子和细胞表面受体参与 ECM 的重塑。MMP 和 ADAM 活性与多种疾病的相关性促使了许多药物开发计划的开展。然而，基于广泛和 Zn 螯合的 MMP 和 ADAM 抑制剂在临床上表现不佳。最近根据 (a) 抗体或抗体片段或 (b) 设计用于利用蛋白酶次级结合位点 (外位) 或别构位点的小分子，已经描述了选择性 MMP 和 ADAM 抑制剂。已经对其中几种抑制剂进行了临床试验，而其他抑制剂则处于先进的临床前阶段。
