Using an unbiased drug discovery platform to uncover a novel immunogenic cell death

SyntheX uses synthetic biology to create the next generation of drug discovery platforms to modulate protein-protein interactions (PPIs). Using genetically engineered circuits, our platform technology relies on intracellular drug selection as opposed to in vitro screening. This allows us to discover compounds with novel modes of action that can engage targets not just in orthosteric but also in allosteric manners. We have developed ToRPPIDO to discover disruptors of PPIs, and ToRNeDO to discover functional protein degraders that are capable of inducing proximity between a ubiquitin E3 ligase and a neosubstrate of interest. The platforms are compatible with multiple chemical matter modalities. We have successfully performed multiple screens with our in-house proprietary DNA encoded peptide and macrocycle libraries, and have additionally established the amenability of our platforms to high-throughput small molecule screening (HTS).

Our lead program, STX100, is a stabilized peptide that targets an intracellular PPI within the homologous recombination (HR) DNA repair pathway. Work on this program led us to discover and characterize a new immunogenic cell death mechanism that exploits the differential abundance of the HR target in cancer cells relative to normal tissue. Upon binding to its target, STX100 elicits an acute calcium-dependent cell death in over 30 different cancer cell lines but not in primary cells. STX100 exhibits in-vivo efficacy in multiple tumor types and potentiates the activity of immune-checkpoint blockade (ICB) therapies in multiple ICB-recalcitrant syngeneic models.