Abstract 1753: GLPG1790: The first Ephrin (EPH) receptor tyrosine kinase inhibitor for the treatment of triple negative breast cancer

Abstract

Abstract Receptor tyrosine kinases define a clinically relevant class of targets in the field of cancer. Here we report the discovery of a pre-clinical drug candidate directed against the EPH receptor family. Members of this family of receptor tyrosine kinases are over-expressed in diverse cancer types. GLPG1790 is a small molecule, nanomolar inhibitor of various EPH receptors kinases. The compound displayed a remarkable efficacy by once-daily oral administration in a mouse EPHA2 expressing xenograft model (MDA-MB-231). A rapid dose-dependent reduction of tumor growth was achieved, with full inhibition at the oral dose of 30 mg/kg/d. GLPG1790 efficacy at this dose was similar to that of Paclitaxel administered at its maximum tolerated dose. A series of experiments was initiated to confirm the mechanism of action of this compound. GLPG1790 inhibits human EPHA2 kinase activity with an IC50 of 11 nM in a biochemical assay. In the human MDA-MB-231 breast cancer cell line, that expresses a high level of EPHA2 protein, GLPG1790 inhibits receptor phosphorylation with an IC50 of 260 nM, and anchorage-independent growth with similar potency. In addition, in vivo target engagement was demonstrated in the mouse MDA-MB-231 xenograft model. GLPG1790 inhibited EPHA2 receptor phosphorylation after single oral administration of 30 and 100 mg/kg doses. The extent of the effects observed on EPHA2 phosphorylation correlated with intra-tumoral GLPG1790 concentration. Moreover, the MAPK pathway, known to be a major driver of proliferation of this cell line, was inhibited both in in vitro cellular assays and in xenograft target engagement studies. Flow cytometric analyses revealed a cell cycle arrest at the G0/G1 phase for MDA-MB-231 cells treated with GLPG1790. EPHA2 knock-down-based experiments further support the EPH-driven mode of action of GLPG1790. All together these data stimulate the development of GLPG1790 in triple negative breast cancer. This novel mechanism of action is under investigation in other cancer types overexpressing EPH's (melanoma, pancreatic, ovarian, prostatic and colorectal cancers). Citation Format: Philippe Pujuguet, Filip Beirinckx, Carole Delachaume, Jacques Huck, Ellen Van der Aar, Reginald Brys, Luc Van Rompaey, Piet Wigerinck, Laurent Saniere. GLPG1790: The first Ephrin (EPH) receptor tyrosine kinase inhibitor for the treatment of triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1753. doi:10.1158/1538-7445.AM2014-1753