March 29, 2011 -- 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, physi-cochemical and in-vitro ADMET properties has led to the identification of small molecular com-pounds with a unique kinase selectivity profile. AEZS-129 was identified as a potent inhibitor of class I PI3Ks lacking activity against mTOR. Lack of mTOR activity is considered to potentially lead to a better safety profile. In biochemical and cellular assays AEZS-129 demonstrates favorable properties in early in-vitro ADMET screening including microsomal stability, plasma stability and screening against a safety profile composed of receptors, enzymes and cardiac ion-channels. In vitro, the compound was shown to be a selective ATP-competitive inhibitor of PI3K with a broad anti-proliferative activity against a broad panel of tumor cell lines. In vivo, AEZS-129 showed excellent plasma exposure and significant tumor growth inhibition in several tumor xenografts models, including A-549 (lung), HCT-116 (colon) and Hec1B (endometrium). In summary, these data suggest, that AEZS-129 is a promising compound for clinical intervention of the PI3K/ Akt pathway in human tumors.
AEZS-131 was established as a small molecular compound that inhibits Erk in the low nanomolar range and shows an excellent selectivity profile. Further characterization experiments revealed an ATP-competitive mode of action and the potent inhibition of the cellular downstream target Rsk1 in tumor cells. The frontrunner AEZS-131 produces cell cycle arrest in G1 and results in growth inhibition of cancer cells. Furthermore, the potential of combination therapy of AEZS-131 with in-hibitors of the PI3K pathway was addressed and the analysis of combination effects on tumor cell proliferation is presented. These results support the evaluation of selective Erk inhibitors as anti-proliferative agents either as monotherapy or in combination with inhibitors of the PI3K/Akt path-way. In vivo studies have been recently conducted, and the results will be presented at the AACR annual meeting in April 2011 in Orlando, Florida.
AEZS-132 is a unique dual inhibitor of PI3K and Erk in the nanomolar range and exerts high se-lectivity against other serine threonine and tyrosine kinases. AEZS-132 is also an ATP-competitive inhibitor, with a broad anti-proliferative profile in vitro, a favorable safety profile and beneficial ADME properties. In-vivo pharmacokinetic experiments showed plasma profiles expected to result in positive in-vivo anti-tumor efficacy, and led to significant anti-tumor activity in mouse xenograft models, including HCT-116 (colon), A-549 (lung), and Hec1B (endometrium). Cellular inhibition of the downstream targets p-Akt and pRsk was confirmed within the in vivo tumor studies. In summary, AEZS-132 is a unique dual kinase inhibitor targeting the PI3K and MAPK pathways expected to be especially suited to treat tumors with over-activation of both pathways.
