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.
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This 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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