CAL-101

The phosphatidylinositol 3-kinase (PI3K) signaling pathway has central roles in cell growth, development, and survival.^1,2 CAL-101 is a cell permeable inhibitor of the PI3K catalytic subunit p110δ (IC₅₀ = 2.5 nM) that demonstrates 40- to 300-fold selectivity against other PI3K class I enzymes (IC₅₀s = 820, 565, and 89 nM for p110α, β, and γ, respectively).³ At 1 μM it can block constitutive PI3K signaling in malignant B-cell lines and primary patient tumor cells, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase, and apoptosis.³ It has also been shown to inhibit the chemotaxis of chronic lymphocytic leukemia cells and to downregulate the secretion of chemokines triggered by B-cell receptor signaling.⁴

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1. Hennessy, B.T., Smith, D.L., Ram, P.T., et al. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discov. 4(12), 988-1004 (2005).

2. Hirsch, E., Ciraolo, E., Ghigo, A., et al. Taming the PI3K team to hold inflammation and cancer at bay. Pharmacol. Ther. 118(2), 192-205 (2008).

3. Lannutti, B.H., Meadows, S.A., Hermann, S.E.M., et al. CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 117(2), 591-594 (2011).

4. Hoellenriegel, J., Meadows, S.A., Sivina, M., et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 118(13), 3603-3612 (2011).