There is an urgent and unmet medical need for development of new therapeutics for acute myeloid leukemia (AML). The anti-apoptotic Bcl-2 family protein Mcl-1 plays a critical role in AML cell survival and chemoresistance. Mcl-1 is upregulated in relapsed AML and leukemic stem cells. Inhibition of Mcl-1 expression in AML cells by kinase inhibitors or gene targeting induces apoptosis and suppresses leukemogenesis. However, the impact of targeting Mcl-1 in AML therapy with selective pharmacological inhibitors remains to be assessed. Recently, we discovered a novel Mcl-1 inhibitor, maritoclax (marinopyrrole A), which antagonizes Mcl-1 by targeting Mcl-1 for proteasomal degradation. This unique mechanism of action is in contrast to BH3 mimetics that exert their inhibitory function through disruption of the interactions between pro- and anti-apoptotic Bcl-2 family proteins. In a panel of AML cell lines, the potency of maritoclax positively correlated with Mcl-1 expression and inversely correlated with Bcl-2 and Bcl-xL expression. Maritoclax was efficacious as a single agent and markedly synergized with ABT-737 to induce apoptosis in Mcl-1 overexpressing ABT-737 and multidrug resistant AML cell lines. Moreover, maritoclax was able to overcome stroma-mediated resistance to apoptosis in AML cells. Importantly, maritoclax induced Mcl-1 degradation and apoptotic cell death selectively in clinical AML specimens with high levels of Mcl-1. To evaluate the anti-tumor activity of maritoclax in vivo, we established U937 tumor xenografts in nude mice. As a single agent, maritoclax significantly inhibited the growth of established xenografts at a dose of 20 mg/kg/d intraperitoneally. At this dosing level, no significant difference in body weight change and complete blood count was observed between maritoclax and vehicle treatment groups. Collectively, our studies demonstrated that maritoclax represents a novel class of Mcl-1 inhibitors and that the selective pharmacological inhibition of Mcl-1 may be a viable approach for the treatment of AML.

Citation Format: Qiang Liu, Kenichiro Doi, Krishne Gowda, Brian M. Barth, David Claxton, Shantu Amin, Thomas P. Loughran, Hong-Gang Wang. Pre-clinical evaluation of Mcl-1 inhibition through maritoclax in acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1807. doi:10.1158/1538-7445.AM2014-1807

©2014 American Association for Cancer Research.
2014