Identification and pre-clinical testing of a reversible cathepsin protease inhibitor reveals anti-tumor efficacy in a pancreatic cancer model.
Identification and pre-clinical testing of a reversible cathepsin protease inhibitor reveals anti-tumor efficacy in a pancreatic cancer model.
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DOI：
10.1016/j.biochi.2010.04.023
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发表时间：
2010-11
期刊：
影响因子：
3.9
通讯作者：
Joyce, Johanna A.
中科院分区：
文献类型：
--
作者：
Elie, Benelita Tina;Gocheva, Vasilena;Shree, Tanaya;Dalrymple, Stacie A.;Holsinger, Leslie J.;Joyce, Johanna A.
蛋白水解活性是癌症发展和进展中的几个关键过程所必需的，包括肿瘤生长、侵袭和转移。因此，已发现高水平的蛋白酶表达和活性与多种人类癌症中的恶性进展和不良患者预后相关。半胱氨酸组织蛋白酶的木瓜蛋白酶家族的成员是在功能上与癌症有关的蛋白酶类别之一。因此，发现有效的组织蛋白酶抑制剂对于抗癌治疗具有相当大的潜力。在这项研究中，我们描述了一种新的，可逆的组织蛋白酶抑制剂，VBY-825，它对组织蛋白酶B，L，S和V具有高效力的鉴定。VBY-825在胰岛癌的临床前模型中进行了测试，发现显着降低肿瘤负荷和肿瘤数量。因此，VBY-825作为一种新的和有效的抗肿瘤药物的鉴定鼓励了组织蛋白酶抑制剂在癌症中的治疗应用。
Proteolytic activity is required for several key processes in cancer development and progression, including tumor growth, invasion and metastasis. Accordingly, high levels of protease expression and activity have been found to correlate with malignant progression and poor patient prognosis in a wide variety of human cancers. Members of the papain family of cysteine cathepsins are among the protease classes that have been functionally implicated in cancer. Therefore, the discovery of effective cathepsin inhibitors has considerable potential for anti-cancer therapy. In this study we describe the identification of a novel, reversible cathepsin inhibitor, VBY-825, which has high potency against cathepsins B, L, S and V. VBY-825 was tested in a preclinical model of pancreatic islet cancer and found to significantly decrease tumor burden and tumor number. Thus, the identification of VBY-825 as a new and effective anti-tumor drug encourages the therapeutic application of cathepsin inhibitors in cancer.
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