title: Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration.
abstract: Syk is a protein tyrosine kinase that couples B-cell receptor (BCR) activation with downstream signaling pathways, affecting cell survival and proliferation. Moreover, Syk is involved in BCR-independent functions, such as B-cell migration and adhesion. In chronic lymphocytic leukemia (CLL), Syk becomes activated by external signals from the tissue microenvironment, and was targeted in a first clinical trial with R788 (fostamatinib), a relatively nonspecific Syk inhibitor. Here, we characterize the activity of two novel, highly selective Syk inhibitors, PRT318 and P505-15, in assays that model CLL interactions with the microenvironment. PRT318 and P505-15 effectively antagonize CLL cell survival after BCR triggering and in nurse-like cell-co-cultures. Moreover, they inhibit BCR-dependent secretion of the chemokines CCL3 and CCL4 by CLL cells, and leukemia cell migration toward the tissue homing chemokines CXCL12, CXCL13, and beneath stromal cells. PRT318 and P505-15 furthermore inhibit Syk and extracellular signal-regulated kinase phosphorylation after BCR triggering. These findings demonstrate that the selective Syk inhibitors PRT318 and P505-15 are highly effective for inhibition of CLL survival and tissue homing circuits, and support the therapeutic development of these agents in patients with CLL, other B-cell malignancies and autoimmune disorders.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77230-1402, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hoellenriegel
authors.forename: G P
authors.initials: GP
authors.lastname: Coffey
authors.forename: U
authors.initials: U
authors.lastname: Sinha
authors.forename: A
authors.initials: A
authors.lastname: Pandey
authors.forename: M
authors.initials: M
authors.lastname: Sivina
authors.forename: A
authors.initials: A
authors.lastname: Ferrajoli
authors.forename: F
authors.initials: F
authors.lastname: Ravandi
authors.forename: W G
authors.initials: WG
authors.lastname: Wierda
authors.forename: S
authors.initials: S
authors.lastname: O'Brien
authors.forename: M J
authors.initials: MJ
authors.lastname: Keating
authors.forename: J A
authors.initials: JA
authors.lastname: Burger
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis; D003514:Cyclohexylamines / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured
chemical_list: C569036:2-(2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide; C571149:4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-(2-aminocyclohexylamino)pyrimidine-5-carboxamide; D003514:Cyclohexylamines; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase