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Ref Type Journal Article
PMID (23220742)
Authors Spurgeon SE, Coffey G, Fletcher LB, Burke R, Tyner JW, Druker BJ, Betz A, DeGuzman F, Pak Y, Baker D, Pandey A, Hollenbach SJ, Sinha U, Loriaux MM
Title 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.
Journal Vol Issue Date Pages Journal Short Title
The Journal of pharmacology and experimental therapeutics 344 2 2013 Feb 378-87 J Pharmacol Exp Ther
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
PRT062607 PRT062607 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
PRT062607 P505-15|BIIB057 SYK Inhibitor 15 PRT062607 is a selective inhibitor of SYK, which may lead to decreased tumor cell growth and increased sensitivity to chemotherapeutics (PMID: 23220742, PMID: 27406873).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References