Positive results for potent anticancer drug
Æterna and its subsidiary Zentaris have reported positive preclinical results of their novel tubulin-inhibitor ZEN-014, a novel pyrazole derivative that was discovered by Zentaris.
Æterna and its subsidiary Zentaris have reported positive preclinical results of their novel tubulin-inhibitor ZEN-014, a novel pyrazole derivative that was discovered by Zentaris.
It represents a new class of small molecule tubulin binders with antiangiogenic properties which are assumed to be novel highly potent anticancer drugs with blockbuster potential.
ZEN-014 inhibits tubulin polymerisation with an IC50 of 1.3microM. The treatment with non-toxic concentrations (10nM) of ZEN-014 inhibits endothelial cell sprouting and vessel formation. Cancer cells (KB/HeLa) were arrested completely in the G2M phase of mitosis at nanomolar concentrations (IC50: 34nM) and subsequently underwent apoptosis.
Several apoptotic parameters as cell membrane alterations, increase of caspase 3 and 7 activity, DNA fragmentation and inactivation of the Bcl-2 protein are detectable in U937
cancer cells after treatment with nanomolar concentrations of ZEN-014. The compound shows an excellent antitumor activity profile in a broad panel of tumor cell lines (average IC50 of 40nM) including paclitaxel and vincristine resistant cells. ZEN-014 exhibits promising in vivo activity in a renal cell carcinoma model at a dose of 50 mg/kg after oral application. 'These excellent results again show the capability of our own drug discovery unit which is the core for the continuous supply of new development candidates and essential for the growth of our company', said Prof Jurgen Engel, executive vice president, global r&d and coo at Æterna, and chairman and managing director of Zentaris.
Based on these in vitro and in vivo activities, ZEN-014 is a promising new candidate for further preclinical development. ZEN-014 combines antiproliferative activity at nanomolar concentrations with strong inhibition of angiogenesis.