Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma

Abstract

BackgroundPharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton’s kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents.MethodsWe evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib. Safety and efficacy of the compound were then evaluated in two xenograft mouse models of B cell lymphoma.ResultsIQS019 simultaneously engaged a rapid and dose-dependent de-phosphorylation of both constitutive and IgM-activated Syk, Lyn, and Btk, leading to impaired cell proliferation, reduced CXCL12-dependent cell migration, and induction of caspase-dependent apoptosis. Accordingly, B cell lymphoma-bearing mice receiving IQS019 presented a reduced tumor outgrowth characterized by a decreased mitotic index and a lower infiltration of malignant cells in the spleen, in tight correlation with downregulation of phospho-Syk, phospho-Lyn, and phospho-Btk. More interestingly, IQS019 showed improved efficacy in vitro and in vivo when compared to the first-in-class Btk inhibitor ibrutinib, and was active in cells with acquired resistance to this latest.ConclusionsThese results define IQS019 as a potential drug candidate for a variety of B lymphoid neoplasms, including cases with acquired resistance to current BCR-targeting therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0447-6) contains supplementary material, which is available to authorized users.

DCZ3301, a novel cytotoxic agent, inhibits proliferation in diffuse large B-cell lymphoma via the STAT3 pathway

“… 45 , 46 It has been reported that the small-molecule inhibitor to Lyn is a novel target for DLBCL patients. 47 , 48 Our results showed DCZ3301 inhibited Lyn activation along with decreased STAT3 activation. More importantly, the protein expressing of phospho-STAT3 in Lyn-OE cells suggests that DCZ3301 induces STAT3 phosphorylation by inhibiting Lyn activation directly in DLBCL.…”

Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma

“…For functional studies, primary tumor cells from five patients were isolated, cryopreserved, and conserved within the hematopathology collection of our institution (Hospital Clínic-IDIBAPS Biobank R121001-094), as previously described. 28 Primary cultures were maintained in complete medium in the presence of the mesenchymal cell line StromaNKTert (Riken BioResource Center) 29 at a 4:1 ratio, to prevent spontaneous ex vivo apoptosis. The ethical approvals for this project, including informed consent from the patients, were granted following the guidelines of the Hospital Clínic Ethics Committee (Institutional Review Board, registration number 2012/7498).…”

“…Whole cell proteins were extracted from 10 7 DLBCL cells as previously described. 28 Proteins (30-50 μg/lane) were subjected to 10–12% sodium dodecylsulfate-polyacrylamide gel electrophoresis, and transferred onto polyvinylidene difluoride membranes (Immobilon-P; Millipore), or nitrocellulose membranes (Amersham Biosciences). Membranes were then incubated with primary and secondary antibodies ( Online Supplementary Materials and Methods ) and visualized on a mini-LAS4000 device (Fujifilm) by enhanced chemiluminescence (ECL, Amersham Life Science).…”

“…DLBCL cells (5×10 6 cells/mL) were cultured for 1 h in culture medium not containing fetal bovine serum but supplemented with 0.5% bovine serum albumin (Sigma-Aldrich), in the presence or absence of 100 μM AMD3100 or IQS-01.01RS, and analyzed for CXCL12-dependent chemotaxis, as previously described. 28 Values are referred to cells cultured without CXCL12.…”

“…For the subcutaneous DLBCL model, SUDHL6-GFP-Luc cells were inoculated subcutaneously in 8-week old NSG female mice as previously. 28,32 Animals were randomly assigned into four cohorts of four mice each and were given a twice daily dose of 1.5 mg/kg CPI203 (intraperitoneally), a daily dose of 2 mg/kg IQS-01.01RS ( per os ), both agents, or an equal volume of vehicle. Tumor engraftment was determined weekly following mice injection with 75 mg/kg D-luciferine (AnaSpec) and bioluminescence imaging (BLI) using an Aequoria Luxiflux device equipped with an ORCA-ER camera (Hamamatsu).…”