title: Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma.
abstract: Pharmacological 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.
  
  
  
  We 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.
  
  
  
  IQS019 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.
  
  
  
  These 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.
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Balsas
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Esteve-Arenys
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Roldán
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Jiménez
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Rodríguez
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: J G
authors.initials: JG
authors.lastname: Valero
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Chamorro-Jorganes
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Barcelona, Spain.
authors.forename: R Puig
authors.initials: RP
authors.lastname: de la Bellacasa
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Teixidó
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Matas-Céspedes
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Moros
authors.affiliation: Department of Pathology, Hematopathology Unit, Hospital Clinic, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Martínez
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.|Department of Pathology, Hematopathology Unit, Hospital Clinic, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Campo
authors.affiliation: Pangaea Biotech S.L., Quiron Dexeus University Hospital, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Sáez-Borderías
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Barcelona, Spain.
authors.forename: J I
authors.initials: JI
authors.lastname: Borrell
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Pérez-Galán
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain.|Department of Pathology, Hematopathology Unit, Hospital Clinic, Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Colomer
authors.affiliation: Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Barcelona, Spain. groue@clinic.ub.es.
authors.forename: G
authors.identifier: 0000-0003-0245-2257
authors.initials: G
authors.lastname: Roué
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051562:Proto-Oncogene Proteins c-bcr / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C000625009:IQS019; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr
keywords: B-NHL; Btk; Cell migration; Lyn; Mouse model; Syk