Proximity-Based Modalities for Biology and Medicine

Abstract

Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of biological processes with high selectivity and has the potential to substantially expand the target space. A plethora of proximity-based modalities to target proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines the diverse mechanisms and molecules based on induced proximity, including protein degraders, blockers, and stabilizers, inducers of protein post-translational modifications, and agents for cell therapy, and discusses opportunities and challenges that the field must address to mature and unlock translation in biology and medicine.

Discovery of Molecular Glue Degraders via Isogenic Morphological Profiling

“…Crucially, the presented experimental and analytical strategy could be adapted to identify proximity-inducing compounds outside the field of targeted protein degradation, which is an active area of research. , Here we focus on targeted protein degradation. Following our focus, we employed quantitative proteomics for the initial target/mechanistic elucidation for hit compounds identified by the isogenic CPA.…”

Chemically induced proximity reveals mechanotransduction of a meiotic checkpoint at the nuclear envelope

“…Chemically induced proximity (CIP) is a versatile experimental tool that takes advantage of cell-permeant small molecules (73). Several CIP approaches have been engineered for protein dimerization in cultured cells (31; 74), but their application in model organisms has been more limited, due to the challenges of delivering the ligands and their impact on physiology. By repurposing the versatile auxin-inducible degradation system, we developed a CIP system that is easy to use and can also capitalize on the plethora of C. elegans strains expressing degron-tagged endogenous proteins.…”

Native Mass Spectrometry: Insights and Opportunities for Targeted Protein Degradation

“…Additionally, it will be very exciting to explore nMS-based TPD studies with nonmammalian systems particularly for infectious diseases where drug resistance is a significant challenge. Finally, while protein degradation was the phenotypic effect of the proximity-inducing agents discussed herein, there are other proximity-inducing agents that deliver alternate cellular outcomes where nMS could also make a valuable contribution to the characterization of these multicomponent biomolecular systems. − The authors of the highlighted case studies all suggest that nMS will play a crucial role in the next frontier of degrader design and development, in part due to the extreme wealth of knowledge that is garnered, and it will be exciting to witness the future impacts that nMS will have on the field.…”