G protein-coupled receptors (GPCRs) are the largest family of receptors that reside on the surface of human cells. These complex receptors mediate many important physiological functions by binding to extracellular ligands and differentially controlling many signaling pathways inside cells. Due to the diversity of this receptor family and their control of a large number of signaling pathways, GPCRs are commonly dysregulated in human diseases, and more than a third of all marketed drugs engage one or more of these receptors. As a result, GPCRs represent one of the largest families of proteins that have been safely and successfully targeted in modern medicine.
Surprisingly few GPCR-targeted therapies have been developed for oncology, despite frequent dysregulation of the receptors and their signaling mediators that control pro-survival and stress signaling pathways that are important in cancer. Furthermore, the clinically validated ability to target GPCRs safely without cytotoxic effects to normal cells represents a significant opportunity for novel therapeutics that contrast with currently available chemotherapies and targeted agents. Imipridones, the chemical class developed by Oncoceutics, are a novel class of anti-cancer compounds that selectively target GPCRs. The first imipridone to enter the clinic is ONC201, which specifically antagonizes the GPCR DRD2. This makes ONC201 the first clinical molecule for oncology that targets a neurotransmitter pathway and raises a few key questions.
At an event hosted by Oncoceutics, Dr. Joshua Allen of Oncoceutics, and Dr. Paul Insel and Dr. Silvio Gutkind of UC San Diego discussed the role that GPCRs play in cancer, and the potential of GPCR targeting agents in oncology.