Abstract 4474: Dual inhibitors for PI3K and Erk induce growth inhibition of tumor cells

Abstract

The Ras/Raf/Mek/Erk and the PI3K-Akt signaling pathways are prime targets for drug discovery in proliferative diseases such as cancer. The results of research to date indicate that both the MAPK and the PI3K signaling pathways represent therapeutic intervention points for the clinical treatment of malignant tumors. Our multi-parameter optimization program for kinase inhibitor selectivity, cellular efficacy, physico-chemical and in-vitro ADMET properties has led to the identification of a small molecular compound class with an uniquely advantageous dual kinase inhibition profile. These ATP competitive compounds inhibit Erk and PI3K in the nanomolar range and exert high selectivity against other serine threonine and tyrosine kinases. The anti-tumor efficacy of these dual kinase inhibitors was evaluated in diverse human tumor cell lines like HCT116, A549, MDA-MB 468, PC-3 and others. Physicochemical and in-vitro ADMET and safety parameters have been widely assessed. Furthermore in-vivo pharmacokinetic experiments showed plasma profiles expected to result in beneficial in-vivo anti-tumor efficacy. Here we present the key characteristics of the compound class that led to the selection of AEZS-132 for in-vivo experiments with tumor bearing nude mice. The optimization of ADME and physicochemical properties such as solubility, permeability and metabolic stability by medicinal chemistry is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4474.

Targeted therapies in development for non-small cell lung cancer

“…[ 179 ] Similarly, the dual PI3K/ERK inhibitor AEZS-132 demonstrated significant activity in several xenograft models. [ 180 ]…”