A pharmacologic inhibitor of the protease Taspase1 effectively inhibits breast and brain tumor growth.
A pharmacologic inhibitor of the protease Taspase1 effectively inhibits breast and brain tumor growth.
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DOI：
10.1158/0008-5472.can-11-2584
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发表时间：
2012-02-01
期刊：
影响因子：
11.2
通讯作者：
Hsieh JJ
中科院分区：
文献类型：
--
作者：
Chen DY;Lee Y;Van Tine BA;Searleman AC;Westergard TD;Liu H;Tu HC;Takeda S;Dong Y;Piwnica-Worms DR;Oh KJ;Korsmeyer SJ;Hermone A;Gussio R;Shoemaker RH;Cheng EH;Hsieh JJ
苏氨酸内肽酶Taspase 1在癌细胞增殖和凋亡中具有关键作用。在这项研究中，我们开发并评估了Taspase 1的小分子抑制剂作为一种新的候选治疗方式。小鼠Taspase 1基因缺失没有产生明显的缺陷，这表明Taspase 1抑制剂在癌症中使用的广泛治疗指数的可能性。我们定义了Taspase 1识别的肽基序，并对NCI多样性文库进行了基于细胞的双荧光蛋白水解筛选，以鉴定Taspase 1抑制剂（TASPINs）。基于二级和三级筛选，确定4-[（4-胂基苯基）甲基]苯基]胂酸NSC 48300是最具特异性的活性化合物。构效关系研究表明，砷酸部分介导Taspase 1抑制的关键作用。额外的基于FRET的动力学分析将NSC 48300表征为Taspase 1的可逆、非竞争性抑制剂（KI = 4.22 μM）。在乳腺癌的MMTV-neu小鼠模型和脑癌的U251异种移植模型中，NSC 48300产生有效的肿瘤生长抑制。我们的研究结果为开发用于癌症治疗的TASPIN提供了初步的临床前概念证明。
The threonine endopeptidase Taspase1 has a critical role in cancer cell proliferation and apoptosis. In this study, we developed and evaluated small molecule inhibitors of Taspase1 as a new candidate class of therapeutic modalities. Genetic deletion of Taspase1 in the mouse produced no overt deficiencies, suggesting the possibility of a wide therapeutic index for use of Taspase1 inhibitors in cancers. We defined the peptidyl motifs recognized by Taspase1 and conducted a cell-based dual-fluorescent proteolytic screen of the NCI diversity library to identify Taspase1 inhibitors (TASPINs). Based on secondary and tertiary screens the 4-[(4-arsonophenyl)methyl]phenyl]arsonic acid NSC48300 was determined to be the most specific active compound. Structure-activity relationship studies indicated a crucial role for the arsenic acid moiety in mediating Taspase1 inhibition. Additional FRET-based kinetic analysis characterized NSC48300 as a reversible, non-competitive inhibitor of Taspase1 (KI = 4.22 μM). In the MMTV-neu mouse model of breast cancer and the U251 xenograft model of brain cancer NSC48300 produced effective tumor growth inhibition. Our results offer an initial preclinical proof of concept to develop TASPINs for cancer therapy.