Definition

An orally bioavailable selective inhibitor of the gamma isoform of phosphoinositide-3 kinase (PI3Kg), with potential immunomodulating and antineoplastic activities. Upon oral administration, PI3Kg inhibitor HS248 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 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.