IPI-549 | Selective PI3Kgamma inhibitor / Immuno-oncology agent

IPI-549 (1693758-51-8) is a potent and highly selective inhibitor of PI3K-γ in both biochemical (IC₅₀ = 16 nM) and cellular (IC₅₀ = 12.2 nM) assays.¹ Macrophage PI3K-γ has been found to be a critical switch between immune stimulation and suppression.² IPI-549 has been used to reshape tumor immune microenvironments and promote cytotoxic T-cell-mediated tumor regression. Resistance to immune checkpoint blockade in 4T1 and B16-GMCSF tumors was overcome when anti-PD-1 or anti-CTLA4 therapies were combined with PI3K-γ inhibition via IPI-549.³ IPI-549 mono-treatment also resulted in tumor growth inhibition in several cancer cell lines.³ IPI-549 has also been shown to modulate P-glycoprotein-mediated multidrug resistance.⁴

References/Citations:

1) Evans et al. (2016) Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-gamma Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate; ACS Med. Chem. Lett. 7 862
2) Kaneda et al. (2016) PI3Kγ is a molecular switch that controls immune suppression; Nature 539 437
3) De Henau et al. (2016); Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells; Nature 539 443
4) De Vera et al. (2019); Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo; Cancer Letters 442 91