PI3K-gamma inhibitor ZX-4081

An orally bioavailable selective inhibitor of the gamma isoform of phosphoinositide-3 kinase (PI3Kg), with potential immunomodulating and antineoplastic activities. Upon oral administration of PI3Kg inhibitor ZX-4081, this agent targets and inhibits the PI3Kg isoform and prevents the activation of the PI3Kg-AKT-mediated signaling pathway. As PI3Kg plays an important role in immune suppression and promotes immunosuppressive myeloid cell polarization during tumor growth and metastasis, the inhibition of PI3Kg may abrogate the immune-suppressive nature in the tumor microenvironment (TME) and impair PI3Kg-AKT-mediated macrophage polarization. This may promote anti-tumor immunity, may increase CD8-positive T-cell activation and M1-like macrophages and may lead to a reduction in cellular proliferation in PI3Kg-expressing tumor cells. By selectively targeting this isoform, PI3K signaling in normal, non-neoplastic cells is minimally impacted or not affected at all, which minimizes the side effect profile for this agent. PI3Kg is highly expressed in leukocytes and plays a critical role in activation of myeloid cells at sites of inflammation and tumorigenesis, T-cell recruitment into the TME, chemokine-mediated chemotaxis and growth factor signaling.