CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability

Abstract

Phosphatidylinositol-3-kinase p110δ serves as a central integration point for signaling from cell surface receptors known to promote malignant B-cell proliferation and survival. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ as a treatment approach for patients with B-cell malignancies. We thus identified 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one (CAL-101), a highly selective and potent p110δ small molecule inhibitor (half-maximal effective concentration [EC(50)] = 8nM). Using tumor cell lines and primary patient samples representing multiple B-cell malignancies, we have demonstrated that constitutive phosphatidylinositol-3-kinase pathway activation is p110δ-dependent. CAL-101 blocked constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis. These effects have been observed across a broad range of immature and mature B-cell malignancies, thereby providing a rationale for the ongoing clinical evaluation of CAL-101.

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

“…18) or CAL-101 (ref. 23), the latter being a highly specific inhibitor that is 40-to 300-fold more selective for PI3Kd than other PI3K class I enzymes 31 (Fig. 2a,b).…”

IL-4 rescues surface IgM expression in chronic lymphocytic leukemia

“…Recent therapeutic breakthroughs have been achieved by using the BTK inhibitor ibrutinib and the PI3Kd inhibitor idelalesib in CLL patients. 19,20 These findings suggest that sIg expression on CLL samples is restored in proliferation centers. However, the molecular mechanism for BCR rescuing remains unknown.…”

Inhibition of PI3Kδ Reduces Kidney Infiltration by Macrophages and Ameliorates Systemic Lupus in the Mouse

“…To study GS-9829 selectivity on class I PI3K isoforms in cell-based assays, we measured Akt phosphorylation (Ser473) in murine embryonic fibroblasts incubated in serum-free medium (2 h), followed by stimulation with platelet-derived growth factor (10 ng/ml PDGF [Cell Signaling], 10 min, 37˚C) for p110a or with LPS (10 mM LPA [Echelon], 10 min, 37˚C) for p110b (40). p-Akt and Akt levels in cell extracts were analyzed by Western blot.…”