Degradation of protein by PROTAC and other strategies

Publication date: Available online 13 August 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Yang Wang, Xueyang Jiang, Feng Feng, Wenyuan Liu, Haopeng SunAbstractAbnormal protein expression or activities are associated with many diseases, especially cancer. Therefore, down-regulating the proteins involved in cancer cell survival proved to be an effective strategy for cancer treatment—a number of drugs based on proteolysis-targeting chimaera (PROTAC) mechanism have demonstrated clinical efficacy. Recent progress in the PROTAC strategy includes identification of the structure of the first ternary eutectic complex, extra-terminal domain-4-PROTAC-Von-Hippel-Lindau (BRD4-PROTAC-VHL), and PROTAC ARV-110 has entered clinical trials for the treatment of prostate cancer in 2019. These discoveries strongly proved the value of the PROTAC strategy. In this review, we summarize recent meaningful research of PROTACs, including the molecular design and optimization strategy as well as clinical application of candidate molecules. We hope to provide useful insights for rational design of PROTACs.Graphical abstractStrategies for protein degradation include simulating misfolded proteins through hydrophobic tagging; causing proteins to be hijacked by E3 ubiquitin ligase and ubiquitinated through proteolysis-targeting chimaeras (PROTAC). Stable PROTAC ternary complex, which forms new protein-protein interactions (PPIs) by protein with E3 ligase, is essential for protein degradation.
Source: Acta Pharmaceutica Sinica B - Category: Cancer & Oncology Source Type: research