Journey of PROTAC: From Bench to Clinical Trial and Beyond.

Abstract

Proteolysis-targeting chimeras (PROTACs) represent a transformative advancement in drug discovery, offering a method to degrade specific intracellular proteins. Unlike traditional inhibitors, PROTACs are bifunctional molecules that target proteins for elimination, enabling the potential treatment of previously "undruggable" proteins. This concept, pioneered by Crews and his team, introduced the use of small molecules to link a target protein to an E3 ubiquitin ligase, inducing ubiquitination and subsequent degradation of the target protein. By promoting protein degradation rather than merely inhibiting function, PROTACs present a novel therapeutic strategy with enhanced specificity and effectiveness, especially in areas such as cancer and neurodegenerative diseases. Since their initial discovery, the field of PROTAC research has rapidly expanded with numerous PROTACs now designed to target a wide range of disease-relevant proteins. The substantial research, investment, and collaboration across academia and the pharmaceutical industry reflect the growing interest in PROTACs. This Review discusses the journey of PROTACs from initial discovery to clinical trials, highlighting advancements and challenges. Additionally, recent developments in fluorescent and photogenic PROTACs, used for real-time tracking of protein degradation, are presented, showcasing the evolving potential of PROTACs in targeted therapy.