Combined Scaffold Evaluation and Systems‐Level Transcriptome‐Based Analysis for Accelerated Lead Optimization Reveals Ribosomal Targeting Spirooxindole Cyclopropanes
Combined Scaffold Evaluation and Systems‐Level Transcriptome‐Based Analysis for Accelerated Lead Optimization Reveals Ribosomal Targeting Spirooxindole Cyclopropanes
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DOI：
10.1002/cmdc.201900266
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发表时间：
2019-09
期刊：
影响因子：
3.4
通讯作者：
Kevin X. Rodriguez;Erin N. Howe;E. Bacher;M. Burnette;Jennifer L. Meloche;J. Meisel;P. Schnepp;Xuejuan Tan;Mayland Chang;J. Zartman;Siyuan Zhang;B. Ashfeld
中科院分区：
文献类型：
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作者：
Kevin X. Rodriguez;Erin N. Howe;E. Bacher;M. Burnette;Jennifer L. Meloche;J. Meisel;P. Schnepp;Xuejuan Tan;Mayland Chang;J. Zartman;Siyuan Zhang;B. Ashfeld
随着进化的耐药性影响治疗疾病的努力，对表现出新的分子作用机制的小分子的需求是至关重要的。在这项研究中，我们将支架定向合成与混合实验和转录组分析相结合，以鉴定通过破坏核糖体功能抑制癌细胞增殖的双螺吲哚环丙烷。这些发现证明了一种综合的、生物启发的合成和测定策略对于加速鉴定一流的癌症治疗候选药物的价值。
With evolutionary drug resistance impacting efforts to treat disease, the need for small molecules that exhibit novel molecular mechanisms of action is paramount. In this study, we combined scaffold‐directed synthesis with a hybrid experimental and transcriptome analysis to identify bis‐spirooxindole cyclopropanes that inhibit cancer cell proliferation through disruption of ribosomal function. These findings demonstrate the value of an integrated, biologically inspired synthesis and assay strategy for the accelerated identification of first‐in‐class cancer therapeutic candidates.