Acalisib

Acalisib (GS-9820, CAL-120) is a potent, isoform-selective PI3K p110δ with IC50 of 12.7 nM, displays >100-fold selectivity over P110α/β/γ, and other class II/III PI3Ks, DNA-PK, mTOR; inhibits anti-FC RI PI3Kδ induced CD63 expression with IC50 of 14 nM in human whole blood with IC50 of 14 nM; induces osteoclast retraction in rat osteoclasts, disrupts actin belts and blocks RANKL-stimulated osteoclast survival.Blood Cancer Phase 2 Clinical (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.