Author: Sáez-Borderías, A ; Colomer, D ; Balsas, P ; Rodríguez, V ; Teixidó, J ; Valero, J G ; Pérez-Galán, P ; Roldán, J ; Esteve-Arenys, A ; Martínez, A ; Campo, E ; de la Bellacasa, R Puig ; Roué, G ; Moros, A ; Jiménez, L ; Borrell, J I ; Matas-Céspedes, A ; Chamorro-Jorganes, A

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.

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Indication	Highest Phase	Country/Location	Organization	Date
B-Cell Lymphoma	Preclinical	ES	Institut d'Investigacions Biomèdiques August Pi I Sunyer	09 Jun 2015

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