AZD3458

AZD3458 is a potent, highly selective, and orally bioavailable small molecule inhibitor of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PI3Kγ). Developed by AstraZeneca, AZD3458 exhibits high selectivity for the PI3Kγ isoform over other class I PI3K isoforms (alpha, beta, and delta). In preclinical oncology models, AZD3458 acts as an immunomodulator by remodeling the immunosuppressive tumor microenvironment. It repolarizes tumor-associated macrophages (TAMs) toward an immunostimulatory phenotype, reduces myeloid-derived suppressor cell (MDSC) and neutrophil activation, and enhances cytotoxic T-cell activation. AZD3458 has demonstrated synergistic anti-tumor efficacy when combined with immune checkpoint inhibitors (such as anti-PD-1 or anti-PD-L1 antibodies) in various syngeneic mouse models of breast, colon, and lung cancers.