Tyrosine kinase associated cell-surface receptors and G-protein-coupled receptors mediate the activation of class I phosphatidylinositol 3-kinases (PI3Ks). Therefore dysregulated, mutated or over-expressed cell-surface receptors often lead to aberrant PI3K activation in a wide spectrum of cancers. Moreover, genetic alterations in the catalytic subunit of PI3K\#945; (PIK3CA), phosphatase and tensin homolog (PTEN) and ras genes are often observed in human tumors and result in over-activation of the PI3K/ Akt pathway. The members of class I PI3Ks have been the focus of the majority of PI3K research, and are therefore well-validated therapeutic targets for intervention in cancers and immune diseases. A new generation of low molecular weight pyridopyrazine compounds has been identified at Aeterna Zentaris as highly potent and selective inhibitors of class I PI3Ks. These PI3K-inhibitors were profiled in biochemical and cellular assays and investigated by in-vivo pharmacokinetic experiments as well as several mouse xenograft cancer models. Here we present the key in-vitro characteristics of AEZS-126 that led to its selection for in-vivo development. AEZS-126 inhibits PI3K\#945; with an IC50 value of 10nM and proved to be a potent inhibitor of Akt phosphorylation in cellular assays. Mode-of-action studies showed that AEZS-126 acts as an ATP competitive compound. The in-vitro anti-proliferative activity against different human tumor cell lines (MDA-MB 468, U87, Hct116, PC-3, A549 and others) was determined, with EC50 values in the nanomolar range. The optimization of kinase selectivity, physico-chemical and ADMET properties led to the identification of AEZS-126 a compound which has a beneficial in-vitro pharmacologic profile for further in-vivo profiling.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3706.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO