Eganelisib

Eganelisib is an inhibitor of PI3Kγ (IC₅₀s = 16, 3,200, 3,500, and >8,400 nM for PI3Kγ, PI3Kα, PI3Kβ, and PI3Kδ, respectively).¹ It is greater than 100-fold selective for PI3Kγ over a panel of 468 mutant and nonmutant protein and lipid kinases, including Class II PI3K isoforms, and a panel of 80 G protein-coupled receptors, ion channels, and transporters at 10 µM. It inhibits phosphorylation of AKT S473 in SKOV3, 786-0, RAW 264.7, and RAJI cells and inhibits migration of bone marrow-derived macrophages (BMDMs) (IC₅₀ = 85 nM). Eganelisib sensitizes doxorubicin-resistant SW620/Ad300 cells to P-glycoprotein (P-gp) substrates, such as paclitaxel (IC₅₀s = 710 and 6.7 nM for paclitaxel alone and in combination with IPI-549, respectively), and increases the level of intracellular paclitaxel in SW620/Ad300 cells.² It also enhances the tumor growth reduction of paclitaxel (Item No. 10461) in an SW620/Ad300 mouse xenograft model when administered at a dose of 3 mg/kg in combination with paclitaxel.

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1. Evans, C.A., Liu, T., Lescarbeau, A., et al. Discovery of a selective phosphoinositide-3-kinase (PI3K)-γ inhibitor (IPI-549) as an immuno-oncology clinical candidate. ACS Med. Chem. Lett. 7(9), 862-867 (2016).

2. De Vera, A.A., Gupta, P., Lei, Z., et al. 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 Lett. 442, 91-103 (2019).