Acalisib

Acalisib is a potent and selective PI3Kδ inhibitor with an IC₅₀ of 12.7 nM. IC50 & Target: IC50: 12.7 nM (PI3Kδ), 1389 nM (PI3Kγ), 3377 nM (PI3Kβ), 5441 nM (PI3Kα)^[1] In Vitro: Acalisib (GS-9820) is more selective for PI3Kδ (IC₅₀=12.7 nM) relative to other PI3K class I enzymes (IC₅₀: PI3Kα, 5,441 nM; PI3Kβ, 3,377 nM; PI3Kγ, 1,389 nM). Acalisib is also 10³-fold more selective against PI3Kδ than against related kinases, such as PI3KCIIβ (IC₅₀>10 nM), hVPS34 (IC₅₀=12.7 μM), DNA-PK (IC₅₀=18.7 μM), and mTOR (IC₅₀>10 nM). In fibroblasts, the PDGF receptor signals through PI3Kα and the GPCR for lysophosphatidic acid (LPA) signals through PI3Kβ. Acalisib reduces PDGF-induced pAkt by only 50% at 11,585 nM, and LPA-induced pAkt by 50% at 2,069 nM. In Vivo: To dissect the relative contribution of PI3Kα and PI3Kδ inhibition in the reduction of obesity, obese hyperphagic ob/ob mice are treated with a selective PI3Kα inhibitor, BYL-719, or with a selective PI3Kδ inhibitor, Acalisib (GS-9820). Remarkably, BYL-719 reduces body weight after 15 days of treatment to a similar extent as CNIO-PI3Ki, whereas Acalisib has no significant effect at the same doses as BYL-719. It should be noted that 10 mg/kg of Acalisib is sufficient to reduce the growth of multiple myeloma xenografts in mice^[2].