Targeted Protein Degradation by Proteolysis Targeting Chimeras

Proteins have long been the therapeutic targets for drug discovery and development. Most current drugs function by binding to the target proteins and inhibit or promote the proteins' functions. In recent years, degradation of a therapeutic protein has emerged as a revolutionary new approach to modulate protein functions and has become of great interest for small molecule drug discovery. The concept of targeted protein degradation by proteolysis targeting chimera (PROTAC) is introduced. A PROTAC molecule is composed of three moieties: the protein ligand, an E3 ligase ligand, and a linker connecting these two. By binding to both the target protein and the E3 ligase, a PROTAC molecule brings these two proteins close enough to facilitate ubiquitin transfer onto the target protein and subsequent proteasome dependent protein degradation. The biological function of the target protein diminishes with the protein. This new mechanism of action offered many unique features, such as being event driven, catalytic in nature, highly potent and selective., and with broad applications in drug discovery. Since publication of the first PROTAC in 2001, this concept has evolved into drug candidates in clinical development. A brief history, with current progress in discovery and clinical development are reviewed. PROTACs targeting androgen receptor are taken as a case study. Novel PROTACs such as photochemically controlled PROTACs (PHOTACs) and antibody-PROTAC conjugate are introduced. The advancing of oral PROTACs ARV-110 and ARV-471 into clinical development achieved proof of concept and represents a big step toward realizing PROTAC drugs. The challenges, potentials, and perspectives are discussed.