Idelalisib CAL-101 Cas 870281-82-6

CAL-101 is a highly selective and potent p110δ inhibitor with IC₅₀ of 2.5 nM, is 40- to 300-fold more selective for p110δ relative to other PI3K class I enzymes (p110α, p110β, and p110γ; IC₅₀ are 820, 565, and 89nM, respectively).CAL-101 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. CAL-101 inhibits LPA-induced pAkt with an EC₅₀ of 1.9 μM. CAL-101 blocks FcϵRI 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-101-induced apoptosis of chronic lymphocytic leukemia (CLL) cells is significant compare with vehicle treatment alone (P<0.001). CAL-101 induces selective cytotoxicity in CLL cells independent of IgVH mutational status or interphase cytogenetics.A significant reduction is observed in the CD11b⁺Ly6G⁺ neutrophils from brain homogenates of bothp110δ^D910A/D910A mice and CAL-101 (40 mg/kg, i.v.) post-treated mice.

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[1]. Lannutti BJ, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood, 2011, 117(2), 591-594.

[2]. Herman SE, et al. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood, 2010, 116(12), 2078-2088.

[3]. Low PC, et al. PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model. Nat Commun. 2014 Mar 14;5:3450.