Shinde Vaibhav, Sureshkumar Poornima, Sotiriadou Isaia, Hescheler Jurgen, Sachinidis Agapios
Institute of Neurophysiology and Centre for Molecular Medicine Cologne (CMMC), Robert-Koch-Str. 39, 50931 Cologne, Germany.
Curr Med Chem. 2016;23(30):3495-3509. doi: 10.2174/0929867323666160627113436.
New drug discovery (NDD) is a fascinating discipline encompassing different facets of medicine, pharmacology, biotechnology and chemistry. NDD is very often restricted by efficacy or safety problems of the new clinical candidate in human patients. Drug regulatory authorities have provided various guidelines for advancement of safe new chemical entities (NCEs) in clinical trials which must be strictly followed. In spite of this, various drugs have failed in clinical trials or withdrawn from market because of human safety issues related to cardiotoxicity, hepatotoxicity, neurotoxicity and teratogenicity. The failure of safety prediction was pointed to species specificity issues, lack of mechanistic toxicity data and inadequate clinical trials. These drugs not only affect human health but also cause loss of resources and time. The species specificity issues are partially addressed by use of primary human cells but their availability is very limited. Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) offer sources for generation of an unlimited number of human somatic cells. The emergence of mechanistic models for toxicity testing with transcriptomics, proteomics along with toxicokinetics readouts based on hESCs and hiPSCs is paving the way to design new human relevant testing strategies. Introduction of these models at the timeframe of lead selection and optimization in parallel with in vitro pharmacokinetic studies will significantly reduce compound attrition rate by selection of safer lead molecules. We focused on upcoming hESCs and hiPSCs based toxicity testing models and their future role to address safety gaps of present drug discovery and development.
新药发现（NDD）是一门引人入胜的学科，涵盖医学、药理学、生物技术和化学的不同方面。新药发现常常受到新临床候选药物在人类患者中的疗效或安全性问题的限制。药品监管机构已提供了各种指导方针，以推进安全的新化学实体（NCE）进入临床试验，必须严格遵循这些指导方针。尽管如此，由于与心脏毒性、肝毒性、神经毒性和致畸性相关的人类安全问题，各种药物在临床试验中失败或退出市场。安全预测的失败归因于物种特异性问题、缺乏机制毒性数据和临床试验不足。这些药物不仅影响人类健康，还会造成资源和时间的损失。通过使用原代人类细胞部分解决了物种特异性问题，但其可用性非常有限。人类胚胎干细胞（hESC）和诱导多能干细胞（hiPSC）为生成无限数量的人类体细胞提供了来源。基于hESC和hiPSC的转录组学、蛋白质组学以及毒代动力学读数的毒性测试机制模型的出现，为设计新的人类相关测试策略铺平了道路。在先导化合物选择和优化阶段引入这些模型，并与体外药代动力学研究并行，将通过选择更安全的先导分子显著降低化合物的淘汰率。我们重点关注即将出现的基于hESC和hiPSC的毒性测试模型及其在解决当前药物发现和开发安全差距方面的未来作用。
