, Belchertown, MA, 01007, USA.
Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia.
J Comput Aided Mol Des. 2021 May;35(5):613-628. doi: 10.1007/s10822-021-00387-5. Epub 2021 May 4.
The Arylhydrocarbon Receptor (AhR), a member of the Per-ARNT-SIM transcription factor family, has been as a potential new target to treat breast cancer sufferers. A series of 2-phenylacrylonitriles targeting AhR has been developed that have shown promising and selective activity against cancerous cell lines while sparing normal non-cancerous cells. A quantitative structure-activity relationship (QSAR) modeling approach was pursued in order to generate a predictive model for cytotoxicity to support ongoing synthetic activities and provide important structure-activity information for new structure design. Recent work conducted by us has identified a number of compounds that exhibited false positive cytotoxicity values in the standard MTT assay. This work describes a good quality model that not only predicts the activity of compounds in the MCF-7 breast cancer cell line, but was also able to identify structures that subsequently gave false positive values in the MTT assay by identifying compounds with aberrant biological behavior. This work not only allows the design of future breast cancer cytotoxic activity in vitro, but allows the avoidance of the synthesis of those compounds anticipated to result in anomalous cytotoxic behavior, greatly enhancing the design of such compounds.
芳香烃受体（AhR）是芳香烃受体核转录因子家族的成员，已被作为治疗乳腺癌患者的潜在新靶标。已经开发了一系列针对 AhR 的 2-苯基丙烯腈，它们对癌细胞系表现出有希望的选择性活性，同时保护正常的非癌细胞。为了生成支持正在进行的合成活性的细胞毒性预测模型并为新结构设计提供重要的结构活性信息，我们采用了定量构效关系（QSAR）建模方法。我们最近的工作确定了许多在标准 MTT 测定中表现出假阳性细胞毒性值的化合物。这项工作描述了一个高质量的模型，不仅可以预测 MCF-7 乳腺癌细胞系中化合物的活性，而且还能够通过鉴定具有异常生物学行为的化合物来识别随后在 MTT 测定中产生假阳性值的结构。这项工作不仅允许设计未来的体外乳腺癌细胞毒性活性，而且允许避免合成那些预期会导致异常细胞毒性行为的化合物，极大地增强了此类化合物的设计。
