Finding Novel Kinases Targets in Oncology at AEterna Zentaris - Development of Inhibitors Targeting the MAPK and PI3K Pathways
Published: Mar 29, 2011
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.