AZD3458 (AZD-3458) is a potent and remarkably selective PI3Kγ inhibitor with pIC50 of 9.1, displays >100-fold selectivity over PI3Kα/β/δ.
AZD3458 exhibits PI3Kγ target engagement cell assay measuring phosphorylation of AKT with pIC50 of 8.1.
AZD3458 enhanced antitumor activity of immune checkpoint inhibitors in 4T1, CT26, and MC38 syngeneic models, increasing CD8+ T-cell activation status.
AZD3458 alone or in combination with PD-1-blocking antibodies promoted an increase in antigen-presenting (MHCII+) and cytotoxic (iNOS+)-activated macrophages, as well as dendritic cell activation.
AZD3458 reduced IL-10 secretion and signaling in primary human macrophages and murine tumor-associated macrophages, but did not strongly regulate IL-12.
AZD3458 shows dose-dependent inhibition of LPS-induced airway neutrophilia in rats.
