1. Academic Validation
  2. 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

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

  • J Pharmacol Exp Ther. 2013 Feb;344(2):378-87. doi: 10.1124/jpet.112.200832.
Stephen E Spurgeon 1 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
Affiliations

Affiliation

  • 1 Knight Cancer Institute, Oregon Health & Science University, 3181 Sam Jackson Park Road, Portland, OR 97239, USA. spurgeos@ohsu.edu
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 IC(50) = 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.

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