蛋白降解靶向嵌合体药物(PROTAC)的非临床评价策略分析

Non-clinical evaluation strategy for proteolysis-targeting chimera(PROTAC) pharmaceuticals

蛋白降解靶向嵌合体(PROTAC)将靶向蛋白募集到E3泛素连接酶进行泛素化标记,然后通过泛素-蛋白酶体途径将其降解,从而将过表达和突变的致病蛋白清除。本文基于已有的文献报道,总结PROTAC药物研发进展,针对其存在的相对分子质量较大、生物利用度低、稳定性和血管穿透能力差等问题提出应对策略,并从药理药效、代谢和安全性评价等方面对该类药物的非临床评价研究需要考虑的问题进行分析,为制定PROTAC药物非临床评价研究方案提供参考。

Proteolysis-targeting chimeras(PROTACs)recruit the target protein to E3 ubiquitin ligase for ubiquitination labeling to degrade it through the ubiquitin-proteasome pathway so as to eliminate the overexpressed or mutated pathogenic protein.A brief overview of research and development of PROTAC pharmaceuticals was given in this paper.Strategies were recommended to address the larger molecular mass,poor stability,low bioavailability and poor penetration of PROTACs.Problems related to non-clinical evaluation that need to be considered in terms of pharmacodynamics,metabolism and safety evaluation were also analyzed in this paper in order to provide reference for the non-clinical evaluation of PROTAC drugs.