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 Tyner, Marc Loriaux, Mike Deininger, Brian Druker, Kamal D. Puri, Roger G. Ulrich, Neill A. Giese

Research output: Contribution to journalArticle

501 Citations (Scopus)

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

Fingerprint

Phosphatidylinositol 3-Kinase
Phosphatidylinositol 3-Kinases
B-Lymphocytes
Cells
Neoplasms
B-Lymphoid Precursor Cells
Poly(ADP-ribose) Polymerases
Cell Surface Receptors
Caspases
Tumor Cell Line
Phosphorylation
Molecules
Cell Survival
Cell proliferation
Therapeutics
Cell Proliferation
Apoptosis
Tumors
Chemical activation
idelalisib

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Lannutti, B. J., Meadows, S. A., Herman, S. E. M., Kashishian, A., Steiner, B., Johnson, A. J., ... 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

CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. / Lannutti, Brian J.; Meadows, Sarah A.; Herman, Sarah E M; Kashishian, Adam; Steiner, Bart; Johnson, Amy J.; Byrd, John C.; Tyner, Jeffrey; Loriaux, Marc; Deininger, Mike; Druker, Brian; Puri, Kamal D.; Ulrich, Roger G.; Giese, Neill A.

In: Blood, Vol. 117, No. 2, 13.01.2011, p. 591-594.

Research output: Contribution to journalArticle

Lannutti, BJ, Meadows, SA, Herman, SEM, Kashishian, A, Steiner, B, Johnson, AJ, Byrd, JC, Tyner, J, Loriaux, M, Deininger, M, Druker, B, Puri, KD, Ulrich, RG & Giese, NA 2011, 'CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability', Blood, vol. 117, no. 2, pp. 591-594. https://doi.org/10.1182/blood-2010-03-275305
Lannutti, Brian J. ; Meadows, Sarah A. ; Herman, Sarah E M ; Kashishian, Adam ; Steiner, Bart ; Johnson, Amy J. ; Byrd, John C. ; Tyner, Jeffrey ; Loriaux, Marc ; Deininger, Mike ; Druker, Brian ; Puri, Kamal D. ; Ulrich, Roger G. ; Giese, Neill A. / CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. In: Blood. 2011 ; Vol. 117, No. 2. pp. 591-594.
@article{1742d1c7199d46f09f95f3c6a3a911e5,
title = "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 [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.",
author = "Lannutti, {Brian J.} and Meadows, {Sarah A.} and Herman, {Sarah E M} and Adam Kashishian and Bart Steiner and Johnson, {Amy J.} and Byrd, {John C.} and Jeffrey Tyner and Marc Loriaux and Mike Deininger and Brian Druker and Puri, {Kamal D.} and Ulrich, {Roger G.} and Giese, {Neill A.}",
year = "2011",
month = "1",
day = "13",
doi = "10.1182/blood-2010-03-275305",
language = "English (US)",
volume = "117",
pages = "591--594",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "2",

}

TY - JOUR

T1 - CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability

AU - Lannutti, Brian J.

AU - Meadows, Sarah A.

AU - Herman, Sarah E M

AU - Kashishian, Adam

AU - Steiner, Bart

AU - Johnson, Amy J.

AU - Byrd, John C.

AU - Tyner, Jeffrey

AU - Loriaux, Marc

AU - Deininger, Mike

AU - Druker, Brian

AU - Puri, Kamal D.

AU - Ulrich, Roger G.

AU - Giese, Neill A.

PY - 2011/1/13

Y1 - 2011/1/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=78751553221&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78751553221&partnerID=8YFLogxK

U2 - 10.1182/blood-2010-03-275305

DO - 10.1182/blood-2010-03-275305

M3 - Article

C2 - 20959606

AN - SCOPUS:78751553221

VL - 117

SP - 591

EP - 594

JO - Blood

JF - Blood

SN - 0006-4971

IS - 2

ER -