New trends in protein degraders that turn “Undruggable” into “Druggable”

Abstract

Chemical knockdown, degradation of specific proteins by small organic compounds, has attracted a great deal of attention in recent drug discovery efforts as a new modality. The “protein degrader” can disrupt the function of a protein by inducing selective proteolysis of the target protein itself, which is a totally different molecular mechanism than those of existing enzyme inhibitors and receptor antagonists. In addition, lenalidomide and fulvestrant, both of which are anticancer agents already on the market and clinically used, also belong to the class of protein degrader, and novel pharmacological effects beyond simple outcomes of conventional enzyme inhibition and receptor antagonism have been indicated. Therefore, it is expected that this new modality might greatly increase the variety of druggable target proteins in drug discovery and development. Here, we outline the technological progress, challenges, and prospects of the protein degraders, which are rapidly being developed in recent years.