Ciallella John R, Reaume Andrew G
Melior Discovery, Inc., Exton, PA, USA.
Melior Discovery, Inc., Exton, PA, USA.
Drug Discov Today Technol. 2017 Mar;23:45-52. doi: 10.1016/j.ddtec.2017.04.001. Epub 2017 May 16.
In vivo phenotypic screening and drug repositioning are strategies developed as alternatives to underperforming hypothesis-driven molecular target based drug discovery efforts. This article reviews examples of drugs identified by phenotypic observations and describes the use of the theraTRACEin vivo screening platform for finding and developing new indications for discontinued clinical compounds. Clinical proof-of-concept for the platform is exemplified by MLR-1023, a repositioned compound that has recently shown significant clinical efficacy in Type 2 diabetes patients. These findings validate an in vivo screening approach for drug development and underscore the importance of alternatives to target and mechanism based strategies that have failed to produce adequate numbers of new medicines.
体内表型筛选和药物重新定位是作为表现不佳的基于假设驱动的分子靶点药物发现努力的替代策略而开发的。本文回顾了通过表型观察鉴定出的药物实例，并描述了theraTRACE体内筛选平台用于为已停产的临床化合物寻找和开发新适应症的用途。该平台的临床概念验证以MLR-1023为例，这是一种重新定位的化合物，最近在2型糖尿病患者中显示出显著的临床疗效。这些发现验证了用于药物开发的体内筛选方法，并强调了替代基于靶点和机制的策略的重要性，因为这些策略未能产生足够数量的新药。
