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.
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.
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, 3181 Sam Jackson Park Road, Portland, OR 97239, USA. spurgeos@ohsu.edu
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Spurgeon
authors.forename: Greg
authors.initials: G
authors.lastname: Coffey
authors.forename: Luke B
authors.initials: LB
authors.lastname: Fletcher
authors.forename: Russell
authors.initials: R
authors.lastname: Burke
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Andreas
authors.initials: A
authors.lastname: Betz
authors.forename: Francis
authors.initials: F
authors.lastname: DeGuzman
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Pak
authors.forename: Dale
authors.initials: D
authors.lastname: Baker
authors.forename: Anjali
authors.initials: A
authors.lastname: Pandey
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Hollenbach
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003514:Cyclohexylamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013154:Spleen / Q000187:drug effects / Q000201:enzymology; D000072377:Syk Kinase; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C571149:4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-(2-aminocyclohexylamino)pyrimidine-5-carboxamide; D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D047908:Intracellular Signaling Peptides and Proteins; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D014740:Vidarabine; C024352:fludarabine