Persistent activation of MYC via genomic translocation or amplification, or via upstream oncogenic signals, underlies the pathogenesis of many aggressive cancers. Myc is still an undruggable oncogene and new therapies that target Myc oncogenic addiction are urgently needed. The translation machinery is a major downstream target of MYC oncogenic activity. Although there are several approved drugs and drug candidates that target translation initiation (including rapamycin, omacetaxine, and zotatifin), targeting the elongation phase of translation is a new, wide-open frontier for cancer drug discovery. Results by UCSF investigators indicate that translation elongation is highly regulated in cancer and represents a selective vulnerability in MYC-driven tumors.
UCSF investigators have designed and synthesized SRA3, an optimized small-molecule modulator of translation elongation, and believe that SRA3 has the potential to be a preclinical development candidate for specific cancers. With exceptional potency and a long drug-target residence time, SRA3 directly modulates the eukaryotic elongation factor-1-alpha (eEF1A), a GTPase that delivers aminoacyl-tRNAs to elongating ribosomes. At low doses, SRA3 selectively stabilizes an eEF1A/ribosome complex and elicits dramatic antitumor effects in mice without significantly affecting global protein synthesis. Current efforts in the Ruggero and Taunton labs are beginning to reveal the molecular mechanisms underlying these effects, as well as specific biomarkers for patient selection.
To develop and commercialize the technology for patient benefit.