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 Spurgeon, Greg Coffey, Luke B. Fletcher, Russell Burke, Jeffrey Tyner, Brian Druker, Andreas Betz, Francis DeGuzman, Yvonne Pak, Dale Baker, Anjali Pandey, Stanley J. Hollenbach, Uma Sinha, Marc Loriaux

Research output: Contribution to journalArticle

31 Citations (Scopus)

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

Fingerprint

B-Cell Chronic Lymphocytic Leukemia
B-Lymphocytes
Non-Hodgkin's Lymphoma
Phosphotransferases
Neoplasms
Splenomegaly
Heterografts
Inhibitory Concentration 50
fludarabine
4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-(2-aminocyclohexylamino)pyrimidine-5-carboxamide
Syk Kinase
In Vitro Techniques
Cell Survival
Healthy Volunteers
Apoptosis
Therapeutics
Growth

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

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. / Spurgeon, Stephen; Coffey, Greg; Fletcher, Luke B.; Burke, Russell; Tyner, Jeffrey; Druker, Brian; Betz, Andreas; DeGuzman, Francis; Pak, Yvonne; Baker, Dale; Pandey, Anjali; Hollenbach, Stanley J.; Sinha, Uma; Loriaux, Marc.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 344, No. 2, 02.2013, p. 378-387.

Research output: Contribution to journalArticle

Spurgeon, Stephen ; Coffey, Greg ; Fletcher, Luke B. ; Burke, Russell ; Tyner, Jeffrey ; Druker, Brian ; Betz, Andreas ; DeGuzman, Francis ; Pak, Yvonne ; Baker, Dale ; Pandey, Anjali ; Hollenbach, Stanley J. ; Sinha, Uma ; Loriaux, Marc. / 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. In: Journal of Pharmacology and Experimental Therapeutics. 2013 ; Vol. 344, No. 2. pp. 378-387.
@article{c9120aecfb4142589de3e58343bd65dd,
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 leukemias",
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.",
author = "Stephen Spurgeon and Greg Coffey and Fletcher, {Luke B.} and Russell Burke and Jeffrey Tyner and Brian Druker and Andreas Betz and Francis DeGuzman and Yvonne Pak and Dale Baker and Anjali Pandey and Hollenbach, {Stanley J.} and Uma Sinha and Marc Loriaux",
year = "2013",
month = "2",
doi = "10.1124/jpet.112.200832",
language = "English (US)",
volume = "344",
pages = "378--387",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - 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

AU - Spurgeon, Stephen

AU - Coffey, Greg

AU - Fletcher, Luke B.

AU - Burke, Russell

AU - Tyner, Jeffrey

AU - Druker, Brian

AU - Betz, Andreas

AU - DeGuzman, Francis

AU - Pak, Yvonne

AU - Baker, Dale

AU - Pandey, Anjali

AU - Hollenbach, Stanley J.

AU - Sinha, Uma

AU - Loriaux, Marc

PY - 2013/2

Y1 - 2013/2

N2 - 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.

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 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.

UR - http://www.scopus.com/inward/record.url?scp=84872695558&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872695558&partnerID=8YFLogxK

U2 - 10.1124/jpet.112.200832

DO - 10.1124/jpet.112.200832

M3 - Article

C2 - 23220742

AN - SCOPUS:84872695558

VL - 344

SP - 378

EP - 387

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -