Tumor cells often evade apoptosis by tipping the balance of Bcl-2 family and BH3-only protein expression towards a more anti-apoptotic environment, thus providing a survival advantage as well as a means of resistance to anti-cancer therapies. Indeed, over-expression of Bcl-2 family members has been shown to confer chemo-resistance in multiple tumor types. One potential result of this survival adaptation, however, is that the tumor cells become dependent on said Bcl-2 family member and hence increasingly vulnerable to targeted pro-apoptotic BH3 mimetics. Clinical validation of this concept has been demonstrated with the Bcl-2/xL inhibitor Navitoclax, where as a single agent in phase I/II trials in relapsed, refractory CLL patients, a 20% response rate was observed. Due to the potential that directly targeting the apoptotic machinery holds in treating cancer, developing BH3 mimetics that easily and effectively combine with standard chemotherapies is an attractive proposition. With this in mind, we have discovered and characterized a novel small molecule BH3 mimetic with nanomolar affinity for Bcl-2 and Bcl-xL. Here we characterize the in vitro and in vivo activity of this inhibitor in a variety of cell types. In addition to exhibiting potent single agent anti-cancer activity, it also potentiates the effectiveness of standard chemotherapeutic agents. Importantly, it also induces regression of sensitive tumors in vivo after a single IV bolus dose. Overall, this novel Bcl-2/xL inhibitor represents an exciting tool to further explore the mechanistic rationale for using potent BH3 mimetics as a foundation therapy across a broad range of tumor types where resistance to standard therapies arises from deregulation of the Bcl-2 family of anti-apoptotic proteins.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2011. doi:1538-7445.AM2012-2011