GPCRs and ClpP in Oncology


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. Biased signaling due to differential receptor-ligand conformations results in distinct downstream effects at GPCR signaling axes that can produce immensely varied clinical safety and/or efficacy profiles and thus has important therapeutic implications. 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. 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. The clinically validated ability to target GPCRs safely without cytotoxic effects to normal cells represents a significant opportunity for novel therapeutics that contrasts with currently available chemotherapies and targeted agents. Selective modulation of GPCRs is challenging due to ligand binding domains that are conserved across functionally divergent, and sometimes opposing, family members. To harness the therapeutic potential of these receptors for the treatment of human cancer, exquisite selectivity is required to enable efficacy and safety that can be achieved through novel target pharmacology.


The mitochondrial protease ClpP degrades mediators of the electron transport chain that carry out oxidative phosphorylation, thereby serving as a critical regulator of bioenergetics in cells. Activation of ClpP can halt oxidative phosphorylation to trigger cell death in certain types of cancer, while normal cells are able to cope due to alternative bioenergetic sources. Selective targeting of ClpP has been proposed as a novel therapeutic target in oncology and other diseases, however this has not been previously evaluated in the clinic.

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.

Click here for scientific literature on GPCRs in oncology.