Abstract B270: Discovery and preliminary characterization of novel tyrosine kinase inhibitors with selectivity to BTK.

Abstract

Bruton's tyrosine kinase (BTK) is a non receptor tyrosine kinase and belongs to the SRC-related TEC subfamily. The role of BTK in the B cell receptor (BCR) signaling pathway is well defined and is critical for full activation of phospholipase-C γ and MAPK as well as calcium mobilization. More than 95% of human lymphomas are B cell lymphoma and among them over 70% expresses BCR. Studies in lymphoma cell lines in vitro have demonstrated the role of BTK in BCR signaling. We have performed in vitro kinase profiling to determine percent inhibition and IC50 for kinase families of interest. An extensive cellular characterization including anti-proliferative assays, Western blot analysis for evaluation of phospho BTK (pY223) and cell cycle analysis was performed in DLBCL TMD8 cells. An in vivo tumor xenograft model was employed to further evaluate the target knockdown and efficacy against tumor growth. Compounds 1 and 2 were found to exhibit potent inhibition of BTK (IC50 0.6 nM), Src family (IC50 0.6-10 nM) and Trk isoforms (IC50 2-4 nM). Inhibition of cell proliferation was accompanied by reduction of phosphorylation of BTK. In addition to the anti-proliferative activity, following a single oral dose, inhibition of BTK phosphorylation (pY223) was observed in vivo in a TMD8 tumor xenograft model. The growth of TMD8 tumor xenografts was markedly suppressed after daily oral administration for 12 days of these two compounds. A series of potent multi non-receptor tyrosine kinase inhibitors targeting the Tec, Src and Trk family of kinases have been discovered and characterized. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B270. Citation Format: Nivedita D. Namdev, Susan Cornell-Kennon, Yi Yu, Jason Hill, Cathy Bull, Laurie Volak, Jianqiang Wang, Deirdre Lowe, Xuibin Gu, Steffi Koerner, Magdi Moussa, David Vensel, Yanbin Liu, Hui Wu, Chang-Rung Chen, Daniel T. Dransfield, Mark A. Ashwell. Discovery and preliminary characterization of novel tyrosine kinase inhibitors with selectivity to BTK. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B270.