Abstract 3254: Novel bivalent Smac mimetics as a new class of anticancer agents

Abstract

Abstract Second mitochondria-derived activator of caspase (Smac) is a protein released from mitochondria in response to apoptotic stimuli which functions as an endogenous inhibitor of several members of inhibitor of apoptotic proteins (IAPs), including XIAP, cIAP-1 and cIAP-2. Smac interacts with IAPs by binding of its N-terminal AVPI tetrapeptide to one or more BIR domains in IAPs. We designed and synthesized a series of non-peptidic, cell-permeable, bivalent small-molecules which mimic the dimeric Smac protein for targeting IAPs (bivalent Smac mimetics) and performed extensive evaluations of these bivalent Smac mimetics for their interaction with IAP proteins and their activity and mechanism of function in cancer cells. Our studies show that these Smac mimetics bind to XIAP, cIAP-1 and cIAP-2 with low nano-molar affinities. They function as extremely potent XIAP antagonists by concurrently targeting both the BIR2 and BIR3 domains of XIAP and nullify its inhibition to both caspase-9 and caspase-3/-7 and potently and effectively induce rapid degradation of these two proteins in cancer cells. The most potent bivalent Smac mimetics inhibit cell growth with IC50 values at low nanomolar and effectively induce apoptosis in a subset of cancer cell lines through TNFα dependent mechanism. Furthermore, bivalent Smac mimetics can dramatically enhance the antitumor activity of TRAIL in both TRAIL-sensitive and -resistant cancer cell lines. The combination of one such bivalent Smac mimetic, SM-164 with TRAIL induces rapid tumor regression in vivo in a breast cancer xenograft model in which either agent is ineffective. Mechanistic studies demonstrate that while RIP1 plays a minimal role in TRAIL's activity as a single agent, it is required for the synergistic interaction between TRAIL and SM-164. XIAP and cIAP1 work in concert to attenuate the activity of TRAIL and SM-164 strongly sensitizes TRAIL by concurrently targeting XIAP and cIAP1. Taken together, our data suggest that bivalent Smac mimetics may have a great therapeutic potential for the treatment of human cancer by targeting multiple IAPs, either alone or in combination with TRAIL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3254. doi:10.1158/1538-7445.AM2011-3254