Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY, 10065, USA.
Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY, 10065, USA.
Cancer Lett. 2019 Dec 28;467:50-57. doi: 10.1016/j.canlet.2019.10.003. Epub 2019 Oct 5.
ADAM proteases are multi domain transmembrane metalloproteases that cleave a range of cell surface proteins and activate signaling pathways implicated in tumor progression, including those mediated by Notch, EFGR, and the Eph receptors. Consequently, they have emerged as key therapeutic targets in the efforts to inhibit tumor initiation and progression. To that end, two main approaches have been taken to develop ADAM antagonists: (i) small molecule inhibitors, and (ii) monoclonal antibodies. In this mini-review we describe the distinct features of ADAM proteases, particularly of ADAM10 and ADAM17, their domain organization, conformational rearrangements, regulation, as well as their emerging importance as therapeutic targets in cancer. Further, we highlight an anti-ADAM10 monoclonal antibody that we have recently developed, which has shown significant promise in inhibiting Notch signaling and deterring growth of solid tumors in pre-clinical settings.
ADAM 蛋白酶是多结构域跨膜金属蛋白酶，可切割一系列细胞表面蛋白，并激活信号通路，这些通路与肿瘤进展有关，包括 Notch、EFGR 和 Eph 受体介导的信号通路。因此，它们已成为抑制肿瘤起始和进展的关键治疗靶点。为此，人们采取了两种主要方法来开发 ADAM 拮抗剂：（i）小分子抑制剂，和（ii）单克隆抗体。在这篇迷你综述中，我们描述了 ADAM 蛋白酶的独特特征，特别是 ADAM10 和 ADAM17，它们的结构域组织、构象重排、调控，以及它们作为癌症治疗靶点的新兴重要性。此外，我们还重点介绍了我们最近开发的一种抗 ADAM10 单克隆抗体，该抗体在抑制 Notch 信号和阻止实体瘤生长方面显示出了显著的前景。
