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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

The Selective Syk Inhibitor P505-15 (PRT062607) Inhibits B Cell Signaling and Function In Vitro and In Vivo and Augments the Activity of Fludarabine in Chronic Lymphocytic Leukemia

Stephen E. Spurgeon, Greg Coffey, Luke B. Fletcher, Russell Burke, Jeffrey W. Tyner, Brian J. Druker, Andreas Betz, Francis DeGuzman, Yvonne Pak, Dale Baker, Anjali Pandey, Stanley J. Hollenbach, Uma Sinha and Marc M. Loriaux
Journal of Pharmacology and Experimental Therapeutics February 2013, 344 (2) 378-387; DOI: https://doi.org/10.1124/jpet.112.200832
Stephen E. Spurgeon
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Greg Coffey
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Luke B. Fletcher
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Russell Burke
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Jeffrey W. Tyner
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Brian J. Druker
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Andreas Betz
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Francis DeGuzman
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Yvonne Pak
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Dale Baker
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Anjali Pandey
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Stanley J. Hollenbach
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Uma Sinha
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Marc M. Loriaux
Laboratories Oregon Health and Science University Knight Cancer Institute, Portland, Oregon (S.E.S., L.B.F., R.B., J.W.T., B.J.D., M.M.L.); Howard Hughes Medical Institute (B.J.D.), and Portola Pharmaceuticals, Inc., South San Francisco, California (G.C., A.B., F.D., Y.P., D.B., A.P., S.H., U.S.)
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Abstract

B-cell receptor (BCR) associated kinases including spleen tyrosine kinase (SYK) contribute to the pathogenesis of B-cell malignancies. SYK is persistently phosphorylated in a subset of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and SYK inhibition results in abrogation of downstream kinase activity and apoptosis. P505-15 (also known as PRT062607) is a novel, highly selective, and orally bioavailable small molecule SYK inhibitor (SYK IC50 = 1 nM) with anti-SYK activity that is at least 80-fold greater than its affinity for other kinases. We evaluated the preclinical characteristics of P505-15 in models of NHL and CLL. P505-15 successfully inhibited SYK-mediated B-cell receptor signaling and decreased cell viability in NHL and CLL. Oral dosing in mice prevented BCR-mediated splenomegaly and significantly inhibited NHL tumor growth in a xenograft model. In addition, combination treatment of primary CLL cells with P505-15 plus fludarabine produced synergistic enhancement of activity at nanomolar concentrations. Our findings support the ongoing development of P505-15 as a therapeutic agent for B-cell malignancies. A dose finding study in healthy volunteers has been completed.

Footnotes

  • B.J.D. is a Howard Hughes Investigator; J.W.T. is supported by grants from the William Lawrence and Blanche Hughes Fund, the Leukemia & Lymphoma Society, the V Foundation for Cancer Research, and National Institutes of Health National Cancer Institute [4R00CA151457-03]. S.E.S. receives funding from the Medical Foundation of Oregon. R.B. is supported by funding from the Division of Hematology and Medical Oncology at Oregon Health & Science University. M.M.L. is supported by grants from the Leukemia and Lymphoma Society and National Cancer Institute [5R21CA159265]. P505-15 was provided by Portola Pharmaceuticals. G.C., A.B., F.D.,Y.P., D.B., A.P., S.H., U.S. are paid employees of Portola Pharmaceuticals and accordingly received support for portions of this research.

  • dx.doi.org/10.1124/jpet.112.200832

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Received October 4, 2012.
  • Accepted December 3, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 2
1 Feb 2013
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Syk Inhibition Augments Fludarabine Activity in CLL

Stephen E. Spurgeon, Greg Coffey, Luke B. Fletcher, Russell Burke, Jeffrey W. Tyner, Brian J. Druker, Andreas Betz, Francis DeGuzman, Yvonne Pak, Dale Baker, Anjali Pandey, Stanley J. Hollenbach, Uma Sinha and Marc M. Loriaux
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 378-387; DOI: https://doi.org/10.1124/jpet.112.200832

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Syk Inhibition Augments Fludarabine Activity in CLL

Stephen E. Spurgeon, Greg Coffey, Luke B. Fletcher, Russell Burke, Jeffrey W. Tyner, Brian J. Druker, Andreas Betz, Francis DeGuzman, Yvonne Pak, Dale Baker, Anjali Pandey, Stanley J. Hollenbach, Uma Sinha and Marc M. Loriaux
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 378-387; DOI: https://doi.org/10.1124/jpet.112.200832
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