Novel chemical modalities for GPCRs

Abstract

G protein-coupled receptors (GPCRs) represent one of the most important classes of therapeutic targets, yet many GPCR-driven diseases remain inadequately addressed by conventional pharmacological approaches. The development of novel chemical modalities (NCMs) offers new opportunities to modulate GPCR function beyond traditional antagonism, enabling innovative strategies to overcome existing therapeutic limitations.

Within this thesis, I report on the design, synthesis and evaluation of NCMs for GPCRs. Specifically, we developed and attempted to optimize molecular degraders for CCR2. Further, we have introduced a novel TPD approach tailored for GPCRs that utilized agonist-induced GPCR internalization followed by E3 ligase recruitment and GPCR degradation. This approach was validated on the A3AR where we displayed its induced internalization and degradation. Lastly, we reported the discovery of novel negative allosteric modulator (NAM) screening hits towards CCR2 and CCR5 using a rapid and cost-effective virtual screening approach coupled with robust medicinal chemistry and receptor pharmacology techniques. Collectively, the novel modalities developed in this thesis explored and validated approaches that can be applied to the vast family of GPCRs. This in turn can lead to strides in deepening our understanding of the life cycle of GPCRs and enable the discovery of innovative GPCR therapeutics.