PT  - JOURNAL ARTICLE
AU  - Stephen E. Spurgeon
AU  - Greg Coffey
AU  - Luke B. Fletcher
AU  - Russell Burke
AU  - Jeffrey W. Tyner
AU  - Brian J. Druker
AU  - Andreas Betz
AU  - Francis DeGuzman
AU  - Yvonne Pak
AU  - Dale Baker
AU  - Anjali Pandey
AU  - Stanley J. Hollenbach
AU  - Uma Sinha
AU  - Marc M. Loriaux
TI  - 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
AID  - 10.1124/jpet.112.200832
DP  - 2013 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 378--387
VI  - 344
IP  - 2
4099  - http://jpet.aspetjournals.org/content/344/2/378.short
4100  - http://jpet.aspetjournals.org/content/344/2/378.full
SO  - J Pharmacol Exp Ther2013 Feb 01; 344
AB  - 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.