Department of Pharmacy, The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China.
College of Biological Science & Engineering, Fuzhou University, Fuzhou, China.
Future Med Chem. 2022 Jan;14(1):35-51. doi: 10.4155/fmc-2021-0246. Epub 2021 Nov 15.
Protease inhibitors are of considerable interest as anticancer agents. Matrix metalloproteinases (MMPs) were the earliest type of proteases considered as anticancer targets. The developments of MMP inhibitors (MMPIs) by pharmaceutical companies can be dated from the early 1980s. Thus far, none of the over 50 MMPIs entering clinical trials have been approved. This work summarizes the reported studies on the structure of MMPs and complexes with ligands and inhibitors, based on which, the authors analyzed the clinical failures of MMPIs in a structural biological manner. Furthermore, MMPs were systematically compared with urokinase, a protease-generating plasmin, which plays similar pathological roles in cancer development; the reasons for the clinical successes of urokinase inhibitors and the clinical failures of MMPIs are discussed.
蛋白酶抑制剂作为抗癌药物具有重要意义。基质金属蛋白酶 (MMPs) 是最早被认为是抗癌靶点的蛋白酶类型。制药公司开发基质金属蛋白酶抑制剂 (MMPI) 可以追溯到 20 世纪 80 年代初。到目前为止，进入临床试验的 50 多种 MMPIs 中没有一种获得批准。这项工作总结了报告的关于 MMPs 及其与配体和抑制剂复合物的结构研究，在此基础上，作者从结构生物学的角度分析了 MMPIs 的临床失败。此外，还系统地比较了 MMPs 与尿激酶，一种产生纤溶酶的蛋白酶，在癌症发展中具有相似的病理作用；讨论了尿激酶抑制剂的临床成功和 MMPIs 的临床失败的原因。
