Idelalisib

Idelalisib (CAL-101, GS-1101) is a potent, selective inhibitor of PI3K p110δ with IC50 of 2.5 nM, 40- to 300-fold selectivity over other class I PI3Ks (p110α/βγ, IC50=820/565/89nM), and 400- to 4000-fold over C2β, hVPS34, DNA-PK, and mTOR; blocks Fc RI p110δ-mediated CD63 expression in basophils with an EC50 of 8 nM; blocks constitutive PI3K signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in PARP and caspase cleavage and an induction of apoptosis in multiple B-cell malignancies.Blood Cancer Approved (In Vitro) :Idelalisib (CAL-101; GS-1101) is a highly selective and potent p110δ inhibitor (EC50=8 nM) . Greater selectivity (400- to 4000-fold) is seen against related kinases C2β, hVPS34, DNA-PK, and mTOR, whereas no activity is observed against a panel of 402 diverse kinases at 10 μM. CAL-101 reduces PDGF-induced pAkt by only 25% at 10 μM. Idelalisib (CAL-101) inhibits LPA-induced pAkt with an EC50 of 1.9 μM. Idelalisib (CAL-101) blocks Fc RI p110δ-mediated CD63 expression with an EC50 of 8 nM, whereas formyl-methionyl-leucyl-phenylalanine activation of p110γ is inhibited with an EC50 of 3 μM. Thus, in cell-based assays, CAL-101 has 240- to 2500-fold selectivity for p110δ over the other class I PI3K isoforms. CAL-101Idelalisib (CAL-101) -induced apoptosis of chronic lymphocytic leukemia (CLL) cells is significant compare with vehicle treatment alone (P<0.001) . Idelalisib (CAL-101) induces selective cytotoxicity in CLL cells independent of IgVH mutational status or interphase cytogenetics. (In Vivo) :A significant reduction is observed in the CD11b+Ly6G+ neutrophils from brain homogenates of bothp110δD910A/D910A mice and Idelalisib (CAL-101) (40 mg/kg, i.v.) post-treated mice.