From classic medicinal chemistry to state‐of‐the‐art interdisciplinary medicine: Recent advances in proteolysis‐targeting chimeras technology

Abstract

Abstract Proteolysis‐targeting chimeras (PROTACs) is a targeted protein degradation (TPD) technique effected by hijacking the ubiquitin‐proteasome system (UPS) of the cells. A PROTAC molecule specifically binds to its protein of interest (POI) and recruits an E3 ligase to assemble a ternary complex. The POI was subsequently ubiquitinated, followed by being degraded by proteasomes. After 20 years of development, PROTAC technology has made a significant progress, and quite some candidates have entered clinical trials. Along with the excitement of realizing that PROTAC technology can develop therapeutics toward those traditionally believed “undruggable” targets; there are still unmet demands in PROTAC design, screening, and intracellular availability. PROTAC technology is rapidly advancing from employing traditional medicinal chemistry methodologies to integrating state‐of‐the‐art chemical biology technologies, becoming a typical example of interdisciplinary medicine. This review summarizes the progress made in PROTAC technology in recent years, including expanding new targets, developing dual‐target PROTACs, rational design and screening strategies, regulatory activation, targeted delivery, and developing biological macromolecule‐contained PROTACs.

Keywords

• PROTAC
• targeted protein degradation
• targeted therapy
• therapeutics development