Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy:advances and perspectives

• 作者: Bin Yu Guochao Liao Yuan Fang
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2020,（7）
• 所属期刊栏目: Reviews
• 页码范围: 1253-1278
• 页数: 26页
• 语种: 英文

摘要

Blocking the MDM2/X-P53 protein-protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers.Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996,SAR405838,NVP-CGM097,MK-8242,RG7112,RG7388,DS-3032b,and AMG232 currently undergo clinical evaluation for cancer therapy.This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points,strategies employed,structure-activity relationship (SAR) studies,binding modes or co-crystal structures,biochemical data,mechanistic studies,and preclinical/clinical studies.Moreover,we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition,acquired resistance and toxicity of P53 activation as well as future directions.