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

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, Neill A. Giese

Research output: Contribution to journalArticle

526 Scopus citations

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 [EC50] = 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.

Original languageEnglish (US)
Pages (from-to)591-594
Number of pages4
JournalBlood
Volume117
Issue number2
DOIs
StatePublished - Jan 13 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Lannutti, B. J., Meadows, S. A., Herman, S. E. M., Kashishian, A., Steiner, B., Johnson, A. J., Byrd, J. C., Tyner, J. W., Loriaux, M. M., Deininger, M., Druker, B. J., Puri, K. D., Ulrich, R. G., & Giese, N. A. (2011). 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. https://doi.org/10.1182/blood-2010-03-275305