Watt Gillian F, Scott-Stevens Paul, Gaohua Lu
Protein Degradation Discovery Performance Unit, Future Pipelines Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
Protein Degradation Discovery Performance Unit, Future Pipelines Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.
Drug Discov Today Technol. 2019 Apr;31:69-80. doi: 10.1016/j.ddtec.2019.02.005. Epub 2019 Mar 23.
Proteolysis Targeting Chimeras (PROTACs) are a rapidly expanding new therapeutic modality inducing selective protein degradation and offering the potential of a differentiated pharmacological profile across multiple therapeutic areas. As the repertoire of protein targets and E3 ligases available for incorporation into PROTACs continues to grow, understanding the drug- and system-dependent parameters for PROTACs will be critical for achieving tissue/cell specific pharmacology. The review discusses the current knowledge and future direction of in vivo PROTAC study evaluation. The importance of establishing the quantitative relationship between loss of protein target and biological function in vivo, coupled with building mechanistic PK/PD and ultimately PBPK/PD models, is emphasised with the aim to aid translation from preclinical to clinical space.
蛋白酶靶向嵌合体（PROTACs）是一种迅速发展的新型治疗方式，可诱导选择性蛋白质降解，并在多个治疗领域具有产生差异化药理学特征的潜力。随着可纳入PROTACs的蛋白质靶点和E3连接酶种类不断增加，了解PROTACs的药物和系统依赖性参数对于实现组织/细胞特异性药理学至关重要。本文综述讨论了体内PROTAC研究评估的当前知识和未来方向。强调了建立体内蛋白质靶点丧失与生物学功能之间定量关系的重要性，以及构建机制性PK/PD模型并最终构建PBPK/PD模型，旨在帮助从临床前研究向临床转化。
