Exploitation of Proximity-Mediated Effects in Drug Discovery: An Update of Recent Research Highlights in Perturbing Pathogenic Proteins and Correlated Issues

Abstract

The utilization of proximity-mediated effects to perturb pathogenic proteins of interest (POIs) has emerged as a powerful strategic alternative to conventional drug design approaches based on target occupancy. Over the past three years, the burgeoning field of targeted protein degradation (TPD) has witnessed the expansion of degradable POIs to membrane-associated, extracellular, proteasome-resistant, and even microbial proteins. Beyond TPD, researchers have achieved the proximity-mediated targeted protein stabilization, the recruitment of intracellular immunophilins to disturb undruggable targets, and the nonphysiological post-translational modifications of POIs. All of these strides provide new avenues for innovative drug discovery aimed at battling human malignancies and other major diseases. This perspective presents recent research highlights and discusses correlated issues in developing therapeutic modalities that exploit proximity-mediated effects to modulate pathogenic proteins, thereby guiding future academic and industrial efforts in this field.

Expanding the horizons of targeted protein degradation: A non-small molecule perspective

“…Since the early 1990s, the concept of inducing proximity through heterobifunctional chimeras has been pivotal in reshaping protein‒biomolecule interactions 209 . Among these innovations, the breakthroughs achieved by PROTACs and molecular glues have been nothing short of revolutionary 22 , 210 . Building on this foundation, recent years have witnessed the emergence of various induced-proximity entities that extend their functionality beyond degradation ( Table 2 ), encompassing targeted protein stabilization and the modulation of PTMs.…”

“…PTMs exert profound influence over myriad cellular processes and pathological states. Recent strides in proximity-inducing modalities have introduced an innovative dimension to PTM regulation, empowering the precise control of processes such as phosphorylation/dephosphorylation, acetylation/deacetylation, and glycosylation/deglycosylation 23 , 209 , 210 , 212 .…”