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 leukemias

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, Marc M. Loriaux

Research output: Contribution to journalArticle

32 Scopus citations

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 5 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 SYKmediated 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.

Original languageEnglish (US)
Pages (from-to)378-387
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume344
Issue number2
DOIs
StatePublished - Feb 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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