Molecular glue degraders: exciting opportunities for novel drug discovery

ABSTRACT

Introduction

Molecular Glue Degraders (MGDs) is a concept that refers to a class of compounds that facilitate the interaction between two proteins or molecules within a cell. These compounds act as bridge that enhances specific Protein-Protein Interactions (PPIs). Over the past decade, this technology has gained attention as a potential strategy to target proteins that were traditionally considered undruggable using small molecules.

Areas Covered

This review presents the concept of cellular homeostasis and the balance between protein synthesis and protein degradation. The concept of protein degradation is concerned with molecular glues, which form part of the broader field of Targeted Protein Degradation (TPD). Next, pharmacochemical strategies for the rational design of MGDs are detailed and illustrated by examples of Ligand-Based (LBDD), Structure-Based (SBDD) and Fragment-Based Drug Design (FBDD).

Expert opinion

Expanding the scope of what can be effectively targeted in the development of treatments for diseases that are incurable or resistant to conventional therapies offers new therapeutic options. The treatment of microbial infections and neurodegenerative diseases is a major societal challenge, and the discovery of MGDs appears to be a promising avenue. Combining different approaches to discover and exploit a variety of innovative therapeutic agents will create opportunities to treat diseases that are still incurable.

KEYWORDS:

• Molecular glue degrader
• targeted protein degradation
• E3 ubiquitin ligase
• chemical biology
• rational design

Article highlights

• Molecular Glue Degraders are small, drug-like compounds that induce Protein-Protein Interactions between an E3 ubiquitin ligase and a Protein of Interest (POI), which result in poly-ubiquitination followed by degradation of the POI.

• Historically, discoveries related to MGDs have frequently occurred by serendipity.

• However, contemporary research has increasingly focused on rational design approaches.

• Classical pharmacochemical approaches such as LBDD, SBDD and FBDD have been investigated to design original MGDs.

• MGDs are emerging as a technology that could help overcome challenges in therapeutics, such as targeting targets that are otherwise considered undruggable with conventional molecules.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.