Antimetastatic activity of a novel mechanism-based gelatinase inhibitor
Antimetastatic activity of a novel mechanism-based gelatinase inhibitor
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DOI：
10.1158/0008-5472.can-04-3570
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发表时间：
2005-05-01
期刊：
影响因子：
11.2
通讯作者：
Fridman, R
中科院分区：
文献类型：
--
作者：
Krüger, A;Arlt, MJE;Fridman, R
基质金属蛋白酶（MMPs），特别是明胶酶（MMP-2和MMP-9），在癌症进展中起着关键作用。然而，MMP抑制剂在癌症患者中的临床试验结果令人失望。尽管有许多原因可以解释临床试验的失败，但缺乏抑制剂的选择性是一个主要的限制。因此，尽管人们一致认为mmp介导的蛋白水解对癌症进展至关重要，并且某些MMPs是干预的重要靶点，但有效和选择性地抑制这些MMPs仍然是药物开发中的主要挑战。我们之前报道了第一个基于机制的MMP抑制剂，命名为SB-3CT，这是一种选择性明胶酶抑制剂。在这里，我们报告了SB-3CT （5-50 mg/kg/d）是一种有效的肝转移抑制剂，可以提高侵袭性t细胞淋巴瘤小鼠模型的存活率。这项研究表明，基于机制的明胶酶抑制代表了一种新的抑制剂设计方法，有望成为一种成功的抗癌疗法。
Matrix metalloproteinases (MMPs), and in particular gelatinases (MMP-2 and MMP-9), play a key role in cancer progression. However, clinical trials in which MMP inhibitors were tested in cancer patients have been disappointing. Whereas many reasons have been postulated to explain the failure of the clinical trials, lack of inhibitor selectivity was a major limitation. Thus, despite the consensus opinion that MMP-mediated proteolysis is essential for cancer progression and that certain MMPs represent important targets for intervention, effective and selective inhibition of those MMPs remains a major challenge in drug development. We previously reported the first mechanism-based MMP inhibitor, designated SB-3CT, which is a selective gelatinase inhibitor. Here we report that SB-3CT (5-50 mg/kg/d) is a potent inhibitor of liver metastasis and increases survival in an aggressive mouse model of T-cell lymphoma. This study shows that mechanism-based inhibition of gelatinases represents a novel approach to inhibitor design that promises to be a successful anticancer therapy.