Potent and selective inhibitors of glutathione S-transferase omega 1 that impair cancer drug resistance.
Potent and selective inhibitors of glutathione S-transferase omega 1 that impair cancer drug resistance.
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DOI：
10.1021/ja2066972
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发表时间：
2011-10-19
影响因子：
15
通讯作者：
Cravatt, Benjamin F.
中科院分区：
文献类型：
--
作者：
Tsuboi, Katsunori;Bachovchin, Daniel A.;Speers, Anna E.;Spicer, Timothy P.;Fernandez-Vega, Virneliz;Hodder, Peter;Rosen, Hugh;Cravatt, Benjamin F.
谷胱甘肽S-转移酶（GST）是一个超家族的酶，其将谷胱甘肽缀合至多种外源和内源化合物以用于生物转化和/或去除。谷胱甘肽S-转移酶ω 1（GSTO 1）在人类癌细胞中高度表达，已表明其在化疗药物的解毒中发挥作用。然而，需要GSTO 1的选择性抑制剂来测试这种酶在癌症和其他（病理）生理过程中所起的作用。考虑到这一目标，我们用GSTO 1和分子库小分子库（MLSMR）300 K+化合物库进行了基于荧光偏振活性的蛋白质谱（fluopol-ABPP）高通量筛选（HTS）。该筛选鉴定了一类GSTO 1的选择性和不可逆的α-氯乙酰胺抑制剂，其被优化以产生具有优异的体外（IC 50 = 21 nM）和原位（IC 50 = 35 nM）效力的失活GSTO 1的试剂KT 53。用KT 53处理的癌细胞显示出对顺铂的细胞毒性作用的高度敏感性，支持GSTO 1在化学治疗剂的解毒中的作用
Glutathione S-transferases (GSTs) are a superfamily of enzymes that conjugate glutathione to a wide variety of both exogenous and endogenous compounds for biotransformation and/or removal. Glutathione S-tranferase omega 1 (GSTO1) is highly expressed in human cancer cells, where it has been suggested to play a role in detoxification of chemotherapeutic agents. Selective inhibitors of GSTO1 are, however, required to test the role that this enzyme plays in cancer and other (patho)physiological processes. With this goal in mind, we performed a fluorescence polarization activity-based protein profiling (fluopol-ABPP) high-throughput screen (HTS) with GSTO1 and the Molecular Libraries Small Molecule Repository (MLSMR) 300K+ compound library. This screen identified a class of selective and irreversible α-chloroacetamide inhibitors of GSTO1, which were optimized to generate an agent KT53 that inactivates GSTO1 with excellent in vitro (IC50 = 21 nM) and in situ (IC50 = 35 nM) potency. Cancer cells treated with KT53 show heightened sensitivity to the cytotoxic effects of cisplatin, supporting a role for GSTO1 in the detoxification of chemo-therapeutic agents
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影响因子：
7.3
作者：
Bachovchin, Daniel A.;Zuhl, Andrea M.;Speers, Anna E.;Wolfe, Monique R.;Weerapana, Eranthie;Brown, Steven J.;Rosen, Hugh;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.
影响因子：
14.8
作者：
Weerapana, Eranthie;Simon, Gabriel M.;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.
影响因子：
2.9
作者：
Board, Philip G.;Coggan, Marjorie;Anders, M. W.
通讯作者：
Anders, M. W.
影响因子：
4.4
作者：
Tabb, DL;McDonald, WH;Yates, JR
通讯作者：
Yates, JR
影响因子：
15
作者：
Adam, GC;Burbaum, J;Cravatt, BF
通讯作者：
Cravatt, BF