Phenotypic Screening of Chemical Libraries Enriched by Molecular Docking to Multiple Targets Selected from Glioblastoma Genomic Data.
Phenotypic Screening of Chemical Libraries Enriched by Molecular Docking to Multiple Targets Selected from Glioblastoma Genomic Data.
复制标题
DOI：
10.1021/acschembio.0c00078
复制
发表时间：
2020-06-19
影响因子：
4
通讯作者：
Meroueh SO
中科院分区：
文献类型：
--
作者：
Xu D;Zhou D;Bum-Erdene K;Bailey BJ;Sishtla K;Liu S;Wan J;Aryal UK;Lee JA;Wells CD;Fishel ML;Corson TW;Pollok KE;Meroueh SO
像大多数实体瘤一样，多形性胶质母细胞瘤(GBM)含有多个过表达和突变的基因，这些基因影响着几个信号通路。抑制像GBM这样的实体瘤的肿瘤生长而没有毒性，可能是通过小分子选择性地调节不同信号通路上的一系列靶点实现的，也称为选择性多药理学。表型筛选可能是发现此类化合物的有效方法，但缺乏创建针对肿瘤靶点的聚焦文库的方法限制了其影响。在这里，我们通过基于结构的分子对接化学文库来创建用于表型筛选的合理文库，该文库针对使用肿瘤RNA序列和突变数据以及细胞蛋白质-蛋白质相互作用数据识别的GBM特定靶点。对包含47个候选者的丰富文库进行筛选后，产生了几种活性化合物，包括1(IPR-2025)，它(1)可抑制低传代患者来源的GBM球体的细胞活力，其微摩尔IC50值为个位数，显著优于标准护理用替莫唑胺；(Ii)抑制Matrigel中内皮细胞的管形成，其IC50值为亚微摩尔；(Iii)对原代造血祖细胞球体或星形胶质细胞活力无影响。RNA测序为1提供了潜在的作用机制，基于质谱学的热蛋白质组图谱证实了该化合物与多个靶点结合。1抑制GBM表型而不影响正常细胞活性的能力表明，我们的筛选方法可能有望产生具有选择性多药理的先导化合物，用于开发像GBM这样的不治之症的治疗。
Like most solid tumors, glioblastoma multiforme (GBM) harbors multiple overexpressed and mutated genes that affect several signaling pathways. Suppressing tumor growth of solid tumors like GBM without toxicity may be achieved by small molecules that selectively modulate a collection of targets across different signaling pathways, also known as selective polypharmacology. Phenotypic screening can be an effective method to uncover such compounds, but the lack of approaches to create focused libraries tailored to tumor targets has limited its impact. Here, we create rational libraries for phenotypic screening by structure-based molecular docking chemical libraries to GBM-specific targets identified using the tumor’s RNA sequence and mutation data along with cellular protein–protein interaction data. Screening this enriched library of 47 candidates led to several active compounds, including 1 (IPR-2025), which (i) inhibited cell viability of low-passage patient-derived GBM spheroids with single-digit micromolar IC50 values that are substantially better than standard-of-care temozolomide, (ii) blocked tube-formation of endothelial cells in Matrigel with submicromolar IC50 values, and (iii) had no effect on primary hematopoietic CD34+ progenitor spheroids or astrocyte cell viability. RNA sequencing provided the potential mechanism of action for 1, and mass spectrometry-based thermal proteome profiling confirmed that the compound engages multiple targets. The ability of 1 to inhibit GBM phenotypes without affecting normal cell viability suggests that our screening approach may hold promise for generating lead compounds with selective polypharmacology for the development of treatments of incurable diseases like GBM.
登录
查看更多内容
影响因子：
4.1
作者：
Kunimoto R;Dimova D;Bajorath J
通讯作者：
Bajorath J
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
14.8
作者：
Arrowsmith CH;Audia JE;Austin C;Baell J;Bennett J;Blagg J;Bountra C;Brennan PE;Brown PJ;Bunnage ME;Buser-Doepner C;Campbell RM;Carter AJ;Cohen P;Copeland RA;Cravatt B;Dahlin JL;Dhanak D;Edwards AM;Frederiksen M;Frye SV;Gray N;Grimshaw CE;Hepworth D;Howe T;Huber KV;Jin J;Knapp S;Kotz JD;Kruger RG;Lowe D;Mader MM;Marsden B;Mueller-Fahrnow A;Müller S;O'Hagan RC;Overington JP;Owen DR;Rosenberg SH;Roth B;Ross R;Schapira M;Schreiber SL;Shoichet B;Sundström M;Superti-Furga G;Taunton J;Toledo-Sherman L;Walpole C;Walters MA;Willson TM;Workman P;Young RN;Zuercher WJ
通讯作者：
Zuercher WJ
影响因子：
5.7
作者：
Arpin CC;Mac S;Jiang Y;Cheng H;Grimard M;Page BD;Kamocka MM;Haftchenary S;Su H;Ball DP;Rosa DA;Lai PS;Gómez-Biagi RF;Ali AM;Rana R;Hanenberg H;Kerman K;McElyea KC;Sandusky GE;Gunning PT;Fishel ML
通讯作者：
Fishel ML
影响因子：
56.9
作者：
Campillos, Monica;Kuhn, Michael;Bork, Peer
通讯作者：
Bork, Peer