1. Academic Validation
  2. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability

CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability

  • Blood. 2011 Jan 13;117(2):591-4. doi: 10.1182/blood-2010-03-275305.
Brian J Lannutti 1 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 Neill A Giese
Affiliations

Affiliation

  • 1 Calistoga Pharmaceuticals Inc, Seattle, WA, USA. blannutti@calistogapharma.com
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.

Figures
Products