Cell based production and selection of PPI-modulating peptides and applications in oncology.
At SyntheX, we have developed ToRPPIDO, a plug-and-play drug discovery platform for the identification of short peptide sequences and macrocycles that are capable of disrupting or bridging protein-protein interactions (PPIs) of interest. The platform uses DNA encoded libraries of peptides and macrocyces, which enables screening a large chemical space in a high throughput manner.
Homology-directed DNA repair (HDR) plays a crucial role in maintaining genomic stability in cancer cells and is typically induced by oncogenes such as Myc, CycE, and KRas. In accordance, overexpression of HDR pathway components correlates with poor prognosis and chemo-resistance in most tumors, including currently untreatable pancreatic and biliary tract cancers. Application of ToRPPIDO towards a crucial PPI within the HDR pathway led to the discovery of STX100, which binds its HDR target with low nanomolar affinity. Subsequent derivatives of STX100 that are cell penetrant and proteolytically stable were tested for selective activity against various cancer cell lines that overexpress HDR. Results from a panel of over 30 cancer and primary cell lines confirm selective cancer cell killing activity of STX100 derivatives in vitro. STX100-mediated cancer cell death is independent of canonical cell death mechanisms (apoptosis, necroptosis, pyroptosis, ferroptosis, etc.). Rather, the mechanism exploits the differential abundance of the HDR target in cancer cells relative to normal tissue to elicit an acute calcium-dependent cell death upon binding of STX100 to its target. ADME/PK studies indicate favorable in-vivo characteristics and further pre-clinical development work is currently ongoing.
Maria Soloveychik is the co-founder and CEO of SyntheX, a therapeutics company focused on accelerating drug discovery using synthetic biology. The company’s core technology, ToRPPIDO, relies on genetic engineering and evolutionary selection to synthesize and identify compounds which modulate protein-protein interactions. SyntheX was founded in 2016 and was incubated at the IndieBio accelerator in San Francisco.
Maria has obtained her PhD from the department of Molecular Genetics at the University of Toronto, where she discovered novel pathways linking metabolism and epigenetic signaling. Maria was previously a member of iGEM and a research scientist at the structural genomics consortium, where her work led to the determination of numerous structures and identification of several drug candidates.