Development of an assay pipeline for the discovery of novel small molecule inhibitors of human glutathione peroxidases GPX1 and GPX4.
Development of an assay pipeline for the discovery of novel small molecule inhibitors of human glutathione peroxidases GPX1 and GPX4.
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开发用于发现人谷胱甘肽过氧化物酶GPX1和GPX4的新型小分子抑制剂的测定管道。
DOI：
10.1016/j.redox.2023.102719
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发表时间：
2023-07
期刊：
影响因子：
11.4
通讯作者：
Hall, Matthew D.
中科院分区：
文献类型：
--
作者：
Cheff, Dorian M.;Cheng, Qing;Guo, Hui;Travers, Jameson;Klumpp-Thomas, Carleen;Shen, Min;Arner, Elias S. J.;Hall, Matthew D.
关键词：
Selenoprotein glutathione peroxidases (GPX), like ubiquitously expressed GPX1 and the ferroptosis modulator GPX4, enact antioxidant activities by reducing hydroperoxides using glutathione. Overexpression of these enzymes is common in cancer and can be associated with the development of resistance to chemotherapy. GPX1 and GPX4 inhibitors have thus shown promise as anti-cancer agents, and targeting other GPX isoforms may prove equally beneficial. Existing inhibitors are often promiscuous, or modulate GPXs only indirectly, so novel direct inhibitors identified through screening against GPX1 and GPX4 could be valuable. Here, we developed optimized glutathione reductase (GR)-coupled GPX assays for the biochemical high-throughput screen (HTS) of almost 12,000 compounds with proposed mechanisms of action. Initial hits were triaged using a GR counter-screen, assessed for isoform specificity against an additional GPX isoform, GPX2, and were assessed for general selenocysteine-targeting activity using a thioredoxin reductase (TXNRD1) assay. Importantly, 70% of the GPX1 inhibitors identified in the primary screen, including several cephalosporin antibiotics, were found to also inhibit TXNRD1, while auranofin, previously known as a TXNRD1 inhibitor, also inhibited GPX1 (but not GPX4). Additionally, every GPX1 inhibitor identified (including omapatrilat, tenatoprazole, cefoxitin and ceftibuten) showed similar inhibitory activity against GPX2. Some compounds inhibiting GPX4 but not GPX1 or GPX2, also inhibited TXNRD1 (26%). Compounds only inhibiting GPX4 included pranlukast sodium hydrate, lusutrombopag, brilanestrant, simeprevir, grazoprevir (MK-5172), paritaprevir, navitoclax, venetoclax and VU0661013. Two compounds (metamizole sodium and isoniazid sodium methanesulfate) inhibited all three GPXs but not TXNRD1, while 2,3-dimercaptopropanesulfonate, PI4KIII beta inhibitor 3, SCE-2174 and cefotetan sodium inhibited all tested selenoproteins (but not GR). The detected overlaps in chemical space suggest that the counter screens introduced here should be imperative for identification of specific GPX inhibitors. With this approach, we could indeed identify novel GPX1/GPX2- or GPX4-specific inhibitors, thus presenting a validated pipeline for future identification of specific selenoprotein-targeting agents. Our study also identified GPX1/GPX2, GPX4 and/or TXNRD1 as targets for several previously developed pharmacologically active compounds.
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影响因子：
2.7
作者：
Eaton JK;Furst L;Cai LL;Viswanathan VS;Schreiber SL
通讯作者：
Schreiber SL
影响因子：
11.4
作者：
Cheff, Dorian M.;Huang, Chuying;Scholzen, Karoline C.;Gencheva, Radosveta;Ronzetti, Michael H.;Cheng, Qing;Hall, Matthew D.;Arner, Elias S. J.
通讯作者：
Arner, Elias S. J.
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
9
作者：
Cheng, Lulin;He, Qingliu;Liu, Bing;Chen, Liang;Lv, Fang;Li, Xuexiang;Li, Yunxue;Liu, Chunyu;Song, Yarong;Xing, Yifei
通讯作者：
Xing, Yifei
DOI：
10.1007/978-1-0716-0163-1_4
发表时间：
2020-01-01
期刊：
TARGETING ENZYMES FOR PHARMACEUTICAL DEVELOPMENT: METHODS AND PROTOCOLS
影响因子：
--
作者：
Baljinnyam, Bolormaa;Ronzetti, Michael;Simeonov, Anton
通讯作者：
Simeonov, Anton