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 is a novel, highly selective and orally bioavailable small-molecule SYK inhibitor (SYK IC50 = 1nM) with anti-SYK activity that is at least 80-fold greater than its affinity for other kinases. We evaluated the pre-clinical 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.
- Received October 4, 2012.
- Revision received December 1, 2012.
- Accepted December 3, 2012.
- The American Society for Pharmacology and Experimental Therapeutics