Shah Falgun, Greene Nigel
Compound Safety Prediction, Pfizer Global Research & Development , 558 Eastern Point Road, Groton, Connecticut 06340, United States.
Chem Res Toxicol. 2014 Jan 21;27(1):86-98. doi: 10.1021/tx400343t. Epub 2013 Dec 11.
The U.S. Environmental Protection Agency (EPA) launched the ToxCast program in 2007 with the goal of evaluating high-throughput in vitro assays to prioritize chemicals that need toxicity testing. Their goal was to develop predictive bioactivity signatures for toxic compounds using a set of in vitro assays and/or in silico properties. In 2009, Pfizer joined the ToxCast initiative by contributing 52 compounds with preclinical and clinical data for profiling across the multiple assay platforms available. Here, we describe the initial analysis of the Pfizer subset of compounds within the ToxCast chemical (n = 1814) and in vitro assay (n = 486) space. An analysis of the hit rate of Pfizer compounds in the ToxCast assay panel allowed us to focus our mining of assays potentially most relevant to the attrition of our compounds. We compared the bioactivity profile of Pfizer compounds to other compounds in the ToxCast chemical space to gain insights into common toxicity pathways. Additionally, we explored the similarity in the chemical and biological spaces between drug-like compounds and environmental chemicals in ToxCast and compared the in vivo profiles of a subset of failed pharmaceuticals having high similarity in both spaces. We found differences in the chemical and biological spaces of pharmaceuticals compared to environmental chemicals, which may question the applicability of bioactivity signatures developed exclusively based on the latter to drug-like compounds if used without prior validation with the ToxCast Phase-II chemicals. Finally, our analysis has allowed us to identify novel interactions for our compounds in particular with multiple nuclear receptors that were previously not known. This insight may help us to identify potential liabilities with future novel compounds.
美国环境保护局（EPA）于2007年启动了ToxCast计划，目的是评估高通量体外试验，以便对需要进行毒性测试的化学物质进行优先级排序。他们的目标是使用一组体外试验和/或计算机模拟特性，为有毒化合物开发预测性生物活性特征。2009年，辉瑞公司加入了ToxCast计划，提供了52种具有临床前和临床数据的化合物，用于在多个可用的试验平台上进行分析。在此，我们描述了ToxCast化学物质（n = 1814）和体外试验（n = 486）空间内辉瑞化合物子集的初步分析。对辉瑞化合物在ToxCast试验组中的命中率进行分析，使我们能够集中挖掘可能与我们化合物损耗最相关的试验。我们将辉瑞化合物的生物活性特征与ToxCast化学空间中的其他化合物进行比较，以深入了解常见的毒性途径。此外，我们探索了ToxCast中类药物化合物与环境化学物质在化学和生物空间中的相似性，并比较了在这两个空间中具有高度相似性的一组失败药物的体内特征。我们发现，与环境化学物质相比，药物在化学和生物空间中存在差异，如果在没有使用ToxCast二期化学物质进行事先验证的情况下，仅基于后者开发的生物活性特征应用于类药物化合物，可能会受到质疑。最后，我们的分析使我们能够识别我们的化合物特别是与多种以前未知的核受体之间的新型相互作用。这一见解可能有助于我们识别未来新型化合物的潜在风险。
