摘要
Targeted protein degradation(TPD)is emerging as a strategy to overcome the limitations of traditional small-molecule inhibitors.Proteolysis-targeting chimera(PROTAC)technology can be used to target proteins by hijacking the ubiquitin-proteasome system.Conceptually,PROTAC aims to target the“undruggable”majority of proteins in the human proteome.Through constant exploration and optimization of PROTACs and the exploitation of other TPD strategies over two decades,TPD has expanded from theoretical studies to clinical strategies,with practical applications in oncological,immunological,and other diseases.In this review,we introduce the mechanisms,features,and molecular targets of orthodox PROTACs and summarize the PROTAC drugs under study as cancer therapeutics in clinical trials.We also discuss PROTAC derivatives and other TPD strategies,such as lysosome-targeting chimeras,autophagy-targeting chimeras,and molecular glue strategies.Collectively,the studies summarized herein support the full potential of TPD in the biomedical industry.
基金
supported by the National Natural Science Foundation of China(82172386 and 81922081 to C.L.)
the Department of Education of Guangdong Province(2021KTSCX104 to C.L.)
the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong Kong-Macao Joint Lab)(2020B1212030006 to A.L.)
the Guangdong Basic and Applied Basic Research Foundation(2022A1515012164 to C.L.)
the Science,Technology and Innovation Commission of Shenzhen(JCYJ20210324104201005 to C.L.).
