Centre of Chemical Biology, Department of Chemistry, Yanbian University, Yanji City, Jilin Province, 133002, China
National Demonstration Centre for Experimental Chemistry Education, Department of Chemistry, Yanbian University, Yanji, Jilin Province, 130002, China
Curr Top Med Chem. 2020;20(27):2459-2471. doi: 10.2174/1568026620666200722104928.
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that play a key role in both physiological and pathological tissue degradation. MMPs have reportedly shown great potentials in the degradation of the Extracellular Matrix (ECM), have shown great potentials in targeting bioactive and imaging agents in cancer treatment. MMPs could provoke Epithelial to Mesenchymal Transition (EMT) of cancer cells and manipulate their signaling, adhesion, migration and invasion to promote cancer cell aggressiveness. Therefore, targeting and particularly inhibiting MMPs within the tumor microenvironment is an effective strategy for cancer treatment. Based on this idea, different MMP inhibitors (MMPIs) have been developed to manipulate the tumor microenvironment towards conditions appropriate for the actions of antitumor agents. Studies are ongoing to improve the selectivity and specificity of MMPIs. Structural optimization has facilitated the discovery of selective inhibitors of the MMPs. However, so far no selective inhibitor for MMP-7 has been proposed.
This study aims to comprehensively review the potentials and advances in applications of MMPs particularly MMP-7 in targeted cancer treatment approaches with the main focus on targeted drug delivery. Different targeting strategies for manipulating and inhibiting MMPs for the treatment of cancer are discussed. MMPs are upregulated at all stages of expression in cancers. Different MMP subtypes have shown significant targeting applicability at the genetic, protein, and activity levels in both physiological and pathophysiological conditions in a variety of cancers. The expression of MMPs significantly increases at advanced cancer stages, which can be used for controlled release in cancers in advance stages.
Moreover, this study presents the synthesis and characteristics of a new and highly selective inhibitor against MMP-7 and discusses its applications in targeted drug delivery systems for therapeutics and diagnostics modalities.
Our findings showed that the structure of the inhibitor P3' side chains play the crucial role in developing an optimized MMP-7 inhibitor with high selectivity and significant degradation activities against ECM.
Optimized NDC can serve as a highly potent and selective inhibitor against MMP-7 following screening and optimization of the P3' side chains, with a Ki of 38.6 nM and an inhibitory selectivity of 575 of MMP-7 over MMP-1.
基质金属蛋白酶（MMPs）是一类锌内肽酶，在生理和病理组织降解中发挥关键作用。据报道，MMPs 在降解细胞外基质（ECM）方面具有巨大潜力，在癌症治疗中靶向生物活性和成像剂方面具有巨大潜力。MMPs 可引发癌细胞上皮间质转化（EMT），并操纵其信号、黏附、迁移和侵袭，以促进癌细胞侵袭性。因此，靶向肿瘤微环境中的 MMPs 并抑制其活性是癌症治疗的有效策略。基于这一理念，已经开发出不同的基质金属蛋白酶抑制剂（MMPI）来操纵肿瘤微环境，使其适合抗肿瘤药物的作用。目前正在进行研究以提高 MMPIs 的选择性和特异性。结构优化促进了 MMPs 选择性抑制剂的发现。然而，迄今为止，尚未提出 MMP-7 的选择性抑制剂。
本研究旨在全面综述 MMPs 特别是 MMP-7 在靶向癌症治疗方法中的潜力和进展，重点是靶向药物递送。讨论了用于操纵和抑制 MMPs 以治疗癌症的不同靶向策略。MMPs 在癌症的所有表达阶段均上调。不同的 MMP 亚型在生理和病理生理条件下的遗传、蛋白质和活性水平上均表现出显著的靶向适用性，在多种癌症中均有应用。MMPs 的表达在癌症晚期显著增加，可用于提前控制晚期癌症的释放。
此外，本研究介绍了一种新型高选择性 MMP-7 抑制剂的合成和特性，并讨论了其在治疗和诊断模式的靶向药物递送系统中的应用。
我们的研究结果表明，抑制剂 P3'侧链的结构在开发高选择性和对 ECM 具有显著降解活性的优化 MMP-7 抑制剂方面起着关键作用。
经过 P3'侧链的筛选和优化，优化后的 NDC 可以作为 MMP-7 的高效且选择性抑制剂，Ki 为 38.6 nM，对 MMP-7 的抑制选择性为 575，对 MMP-1 的抑制选择性为 1。
