Poster on dual Erk/PI3K inhibitors presented at AACR 2010

In Vitro and In Vivo Data Show AEZS-126 as a Promising Oral Compound for Future Clinical Development in Cancer

Aeterna Zentaris Inc. ( AEZS, TSX: AEZ) (the "Company"), a late-stage drug development company specialized in oncology and endocrine therapy, today presented a poster on dual Erk/PI3K inhibitors and made an oral presentation on its selective Erk inhibitors, at the American Association for Cancer Research (AACR) Annual Meeting in Washington, D.C.

Oral Presentation, Abstract #3856

Entitled, "A highly selective Erk-inhibitor with antiproliferative efficacy and the potential for combination therapy with modulators of the PI3K pathway", I. Seipelt, L. Blumenstein, S. Baasner, G. Mueller, B. Aicher, M. Teifel, E. Guenther, M. Gerlach, the presentation outlines data on selective Erk inhibitors as antiproliferative agents either as monotherapy or in combination with inhibitors of the PI3K/Akt pathway.

Results

Aeterna Zentaris has identified small molecular compounds that inhibit Erk in the low nanomolar range and show an excellent selectivity profile. Other serine threonine, lipid or tyrosine kinases are not inhibited at concentrations up to 10(micro)M. Further studies revealed an ATP competitive mode of action and the potent inhibition of the cellular downstream target Rsk1 in tumor cells with an IC50 value of 158nM. The lead structure 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 inhibitors of the PI3K pathway was addressed and synergistic anti-proliferative activity was observed e.g. with the selective PI3K inhibitor, AEZS-126.

Conclusion

These results support further evaluation of selective Erk inhibitors as antiproliferative agents either as monotherapy or in combination with inhibitors of the PI3K/Akt pathway.

Poster #4474

Entitled, "Dual inhibitors for PI3K and Erk induce growth inhibition of tumor cells", I. Seipelt, M. Gerlach, S. Baasner, L. Blumenstein, G. Mueller, B. Aicher, E. Guenther, M. Teifel, the poster focuses on key characteristics of the compound class that led to the selection of AEZS-132 for in vivo evaluation.

Results

A multi-parameter optimization program for kinase inhibitor selectivity, cellular efficacy, physicochemical and in vitro ADMET properties has led to the discovery 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. For the frontrunner compound, AEZS-132, antitumor efficacy was demonstrated in several human tumor cell lines including HCT116, A549, MDA-MB 468, and PC-3. In in vivo antitumor studies, significant antitumor activity was observed at 30 mg/kg daily oral administration of AEZS-132 in HCT116 and Hec1B tumor xenografts, with T/C values of 0.33 (HCT116) and 0.57 (Hec1B), respectively. Furthermore, target modulation has been demonstrated in tumor samples.

Conclusion

The optimization of Aeterna Zentaris' pyridopyrazine compounds towards dual inhibition of PI3K and Erk resulted in the identification of AEZS-132, a unique dual inhibitor of PI3K and Erk with a favourable pharmacology and ADMET profile for further evaluation as an antitumor agent.

Juergen Engel, Ph.D., President and CEO of Aeterna Zentaris stated, "These results not only demonstrate the potential of Erk/PI3K inhibitor compounds as novel treatments in oncology, but also position us as a leading player in this field beyond perifosine, our Akt-inhibitor currently in Phase 3 trials for multiple myeloma and colorectal cancer."