Smac Mimetics: Mechanisms of Action
TetraLogic's lead Smac mimetic TL32711 is a small molecule peptidomimetic of Smac that potently and specifically antagonizes multiple inhibitors of apoptosis proteins (IAPs), resulting in caspase-dependent apoptosis and inactivation of NF-κB survival signaling.
cIAP-1 Degradation:
TL32711 rapidly degrades cIAPs and enables microenvironment cytokines (TNF-α, TRAIL) to activate the extrinsic apoptosis pathway, while it rapidly turns off the canonical NF-κB survival pathway, causing cancer cell death.
TL32711 potently induces cancer cell death with adequate cIAP target suppression and induction of death-receptor cytokine TNF-α. When combined with anti-cancer therapies that induce TNF-α or TRAIL, the anti-tumor activity of the TL32711 combination is significantly enhanced.
XIAP Antagonism:
TL32711 removes XIAP from caspase 3 at the terminus of the extrinsic and intrinsic apoptosis pathways. The intrinsic apoptosis pathway is activated by many types of cytotoxic and targeted cancer therapeutics.
Inhibitors of Apoptosis Proteins (IAPs) Block Apoptotic Cell Death in Tumor Cells by Inhibiting Apoptosis and Activating Survival Pathways
The IAPs (cIAP1, cIAP2 and XIAP) are key regulators of apoptotic or programmed cell death in cells. Apoptosis can be activated by the extrinsic pathway that is triggered by death ligands such as TNFα and TRAIL or via the intrinsic pathway by effects on the mitochondria leading to the activation of caspases. When the IAPs are present in cells that are exposed to the death ligands or intrinsic pathway activators, they activate NF-κB mediated cell survival pathways and block caspase activity, thereby preventing apoptosis.
TL32711 Binds with High Specificity and Affinity to the IAPs in Tumor Cells and Inhibits their Function Leading to the Activation of Apoptotic Cell Death and Shut Down of the Survival Pathways
TL32711 is a mimic of Smac, the natural inhibitor of IAPs in cells. In the presence of TL32711, cIAP1 and cIAP2 are rapidly degraded, leading to a shutdown in cell survival signaling and rapid activation of caspases, resulting in apoptosis in cells exposed to the death ligands TNFα and TRAIL. TL32711 also relieves the XIAP inhibition of caspases, contributing to an increase in activated executioner caspases 3 and 7. The combined effects of TL32711 on the three IAPs result in rapid apoptotic cell death in susceptible tumor cells while leaving normal cells unaffected.
