The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
J Am Chem Soc. 2011 Oct 19;133(41):16605-16. doi: 10.1021/ja2066972. Epub 2011 Sep 27.
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 (IC(50) = 21 nM) and in situ (IC(50) = 35 nM) potency. Cancer cells treated with KT53 show heightened sensitivity to the cytotoxic effects of cisplatin, supporting a role for GSTO1 in chemotherapy resistance.
谷胱甘肽 S-转移酶（GSTs）是一个超家族的酶，它将谷胱甘肽与各种外源和内源化合物共轭，用于生物转化和/或去除。谷胱甘肽 S-转移酶ω 1（GSTO1）在人类癌细胞中高度表达，有人认为它在化疗药物的解毒中起作用。然而，需要选择性 GSTO1 抑制剂来测试该酶在癌症和其他（病理）生理过程中的作用。考虑到这一目标，我们使用 GSTO1 和分子文库小分子库（MLSMR）300K+化合物库进行了荧光偏振活性基蛋白谱（fluopol-ABPP）高通量筛选（HTS）。该筛选鉴定了一类选择性和不可逆的 GSTO1α-氯乙酰胺抑制剂，对其进行了优化，生成了一种名为 KT53 的化合物，该化合物具有优异的体外（IC50=21 nM）和原位（IC50=35 nM）效力，可使 GSTO1 失活。用 KT53 处理的癌细胞对顺铂的细胞毒性作用更加敏感，支持 GSTO1 在化疗耐药中的作用。
