Preclinical characterization of HEC116094, an oral inhibitor of the influenza A virus polymerase PB2 subunit

Influenza A virus remains a global health threat due to its high mutation rate and its resistance to existing neuraminidase and polymerase inhibitors. The polymerase basic protein 2 (PB2) subunit is a promising target for novel therapeutics due to its critical role in inhibiting viral transcription and replication. Here, we reported the preclinical characterization of HEC116094, a novel PB2 inhibitor, against influenza A virus. HEC116094 exhibited potent in vitro activities against multiple laboratory strains (IC50: 0.012–0.069 nM) and the highly pathogenic avian influenza strains H5N1 and H7N9 (IC50: 0.071–0.122 nM). These activities are more potent than VX-787 (Pimodivir) and oseltamivir. Our studies demonstrated that HEC116094 treatment could reduce the extent of weight loss and maintain a 100% survival rate in BALB/c mice, even when initiated 72 h post-infection. In addition, HEC116094 exerted potent in vitro synergy and in vivo therapeutic benefits when combined with oseltamivir. Furthermore, HEC116094 displayed minimal kinase inhibition and excellent PK characteristics. Superior preclinical activity demonstrated that HEC116094 was a more potent PB2 inhibitor against influenza A virus than VX-787 in this study. Currently, HEC116094 is under evaluation in Phase I clinical studies.