CAL-101 (Idelalisib, GS-1101), is a p110δ selective phosphatidylinositol-3-kinase inhibitor in a kinome-wide screen using purified enzymes and in cell-based PI3K isoform-specific assays. 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. CAL-101 can block constitutive phosphatidylinositol-3-kinase signaling, resulting in reduced phosphorylation of Akt and other downstream effect factors, 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. In addition, CAL-101 abrogated protection from spontaneous apoptosis induced by B cell–activating factors CD40L, TNF-α, and fibronectin.
Reference
[1].Brian J. Lannutti, Sarah A. Meadows, Sarah E. M. Herman, Adam Kashishian, Bart Steiner, Amy J. Johnson, John C. Byrd, Jeffrey W. Tyner, Marc M. Loriaux, Mike Deininger, Brian J. Druker, Kamal D. Puri, Roger G. Ulrich, and Neill A. Giese. CAL-101, a p110δ 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].Sarah E. M. Herman, Amber L. Gordon, Amy J. Wagner, Nyla A. Heerema, Weiqiang Zhao, Joseph M. Flynn, Jeffrey Jones, Leslie Andritsos, Kamal D. Puri, Brian J. Lannutti, Neill A. Giese, Xiaoli Zhang, Lai Wei, John C. Byrd, Amy J. Johnson. 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 – 88.