Incorporation of Phenyl Bioisosteres for Innovative Drug Design in Targeted Protein Degradation

Paszczuk, Lauren Chisholm (2025) Incorporation of Phenyl Bioisosteres for Innovative Drug Design in Targeted Protein Degradation. Masters by Research thesis (MPhil), Manchester Metropolitan University.

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Abstract

The global community currently faces a significant health crisis, whereby previously effective therapeutics have become outsmarted by diseases, resulting in a wide range of issues from antibiotic resistance to malignant mutagenesis. The development of novel therapeutics has become a necessary avenue in order to address these challenges, and targeting biological targets, previously thought to be ‘undruggable’, is a key component to this solution. The ubiquitin proteasome system (UPS) has become a vital pathway to target the interactions between proteins to afford the subsequent removal of specific disease-causing proteins (neosubstrates) via their degradation and its dysregulation has been observed in multiple diseases such as cancer. A number of small molecules have shown to be effective tools in the modulation of this pathway and selective protein degradation; these molecules are known as molecular glues and PROteolysis TArgeting Chimeras (PROTACs). This avenue in drug discovery is known as targeted protein degradation (TPD). Despite many recent efforts into improving the physiochemical properties of these molecules, they still encounter issues regarding toxicity, poor solubility and non-selectivity resulting in off-target effects. The incorporation of phenyl bioisosteres into drug discovery has proven fruitful in other applications, however their incorporation has not yet been applied into the TPD field. This study provides insight into the synthetic routes into the incorporation of bicyclo[1.1.1]pentanes (BCPs) for the development of novel targeted protein degraders. A range of BCP-containing compounds were synthesised with yields ranging from 18-98% using optimised pathways that accessed key intermediates. All of the synthesised compounds were fully characterised by nuclear magnetic resonance (NMR).