In Vitro and In Vivo Data Show AEZS-126 as Promising Oral Compound for
Future Clinical Development in Cancer
QUEBEC CITY, April 21 /PRNewswire-FirstCall/ - AEterna Zentaris Inc. , a global biopharmaceutical company focused on endocrine therapy and oncology, today presented two posters on AEZS-126, a promising compound for clinical intervention of the PI3K/ Akt pathway in human tumors. The posters were presented at the American Association for Cancer Research (AACR) Annual Meeting in Denver, Colorado.
Poster #3705
Entitled, “AEZS-126, a new orally bioavailable PI3K inhibitor with antitumor effects”, I. Seipelt, S. Baasner, M. Gerlach, M. Teifel, J. Fensterle, L. Blumenstein, G. Mueller and E. Guenther, the poster focuses on ADMET and safety profiling of the compound, as well as in vivo pharmacokinetic experiments and mouse xenograft antitumor studies.
Results
AEZS-126 was identified as a potent inhibitor of class I PI3Ks in biochemical and cellular assays and demonstrated favorable properties in early in vitro ADMET screening including microsomal stability, plasma stability and screening against a large safety profile composed of receptors, enzymes and cardiac ion-channels. During the course of in vivo pharmacokinetic experiments and mouse xenograft antitumor studies, the oral bioavailability in mice was determined to be about 60%, leading to micromolar plasma levels which are well above the nanomolar IC50 values in in vitro studies. Significant antitumor activity was observed at 30mg/kg daily oral administration in Hct116 and A549 models.
Conclusion
These data suggest that AEZS-126 is a promising compound for clinical intervention of the PI3K/Akt pathway in human tumors.
Poster #3706
Entitled, “In vitro profiling of the potent and selective PI3K inhibitor, AEZS-126", I. Seipelt, M. Gerlach, L. Blumenstein, G. Mueller, M.Teifel, E. Polymeropoulos and E. Guenther, the poster outlines the key in vitro characteristics of this compound that led to its selection for in vivo development.
Results
AEterna Zentaris has identified a new generation of low molecular weight pyridopyrazine compounds as highly potent and selective inhibitors of class I PI3Ks. Presented here, are the key in vitro characteristics of AEZS-126 that led to its selection for in vivo development. AEZS-126 inhibits PI3Ka 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 antiproliferative 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.
Conclusion
The optimization of AEterna Zentaris’ pyridopyrazine lead structure regarding kinase selectivity, cellular potency and ADMET properties, led to the identification of AEZS-126, a compound which has a favorable in vitro pharmacologic profile for further in vivo profiling.
About AEterna Zentaris Inc.
AEterna Zentaris Inc. is a global biopharmaceutical company focused on endocrine therapy and oncology, with proven expertise in drug discovery, development and commercialization. News releases and additional information are available at www.aezsinc.com.
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