Design and synthesis of a protein degradation agent文献综述

Introduction

Traditional approaches in the development of small-molecule drugs typically aim to inhibit the biochemical activity of functional protein domains. In contrast, targeted protein degradation aims to reduce overall levels of disease-relevant proteins (1). Mechanistically, this can be achieved via chemical ligands that induce molecular proximity between an E3 ubiquitin ligase and a protein of interest, leading to ubiquitination and degradation of the protein of interest (2). This paradigm-shifting pharmacology promises to address several limitations inherent to conventional inhibitor design. Most notably, targeted protein degradation has the potential not only to expand the druggable proteome beyond the reach of traditional competitive inhibitors but also to develop therapeutic strategies of unmatched selectivity (3).

The precise control of protein abundance represents a major mechanism of cellular regulation, and is determined by the parallel action of Proximity and interactions between proteins pathways of protein synthesis and protein degradation. The discovery of the ubiquitin-proteasome system (UPS) dramatically changed the view of Protein degradation to be a relatively non-specific process (5).

The Work over several decades has established the UPS as a complex, potent, and versatile means for regulating protein abundance by targeting the substrate protein to the proteasome, a large multi subunit protease that recognizes, unfolds, and ultimately destroys the substrate protein (6).

Targeted destruction of these critical proteins thus serves as a powerful means of regulating cellular function. Misfolded proteins represent a second major class of substrates for the UPS due to their potential toxicity to cells, their timely recognition and destruction by the UPS are critical to cellular well-being (7).

UPS have unraveled, the everincreasing understanding of the relevance of protein degradation for human disease and leaving their dynamic modulation as an important goal in chemical biology and ligand discovery leading to Several innovated strategies to induce protein protein interactions (PPIs).

Regulated protein degradation has emerged as a powerful means of precisely controlling individual protein abundance within cells and is largely mediated by the ubiquitin-proteasome system (UPS). By controlling the levels of key regulatory proteins, the UPS contributes to nearly every aspect of cellular function. The UPS also functions in protein quality control, rapidly identifying and destroying misfolded or otherwise aberrant proteins that may be toxic to cells. Increasingly, we understand that dysregulation of protein degradation pathways is critical for many human diseases. Conversely, the versatility and scope of the UPS provides opportunities for therapeutic intervention (8).

Chemical biologists have devised elegant solutions to modulate protein stability using engineered cellular systems, but these approaches have been limited to non

Endogenous fusion proteins others achieved the degradation of endogenous proteins through the recruitment of E3 ligases, but these approaches have been limited by the requirement of peptide ligands (9-11), the use of nonspecific inhibitors (12-16) and by low cellular potency. We hypothesized the rational design of bifunctional conjugated ligands could confer CRBN-dependent target protein degradation as chemical adapters.

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