[9][10][11] This cleavage also exposes four residues at the N-terminal, Ala-Val-Pro-Ile (AVPI), which is the core of the IAP binding domain and crucial for inhibiting XIAP.

[9][10][11] The homodimer structure also facilitates SMAC-XIAP binding via the BIR2 domain, though it does not form until the protein is released into the cytoplasm as a result of outer mitochondrial membrane permeabilization.

[7][10] Two known isoforms both lack the MTS and the IAP binding domain, suggesting differential subcellular localization and function.

[9] Notably, preclinical studies indicate that the use of SMAC mimetics in conjunction with chemotherapy, death receptor ligands and agonists, as well as small molecule targeted drugs enhance the sensitivity of tumor cells to these treatments.

[9][13][16] In addition to improving the success of tumor elimination, this increased sensitivity can permit smaller doses, thus minimizing side effects while maintaining efficacy.

[16] Nonetheless, there still exists the potential for side effects, such as elevated levels of cytokines and chemokines in normal tissues, depending on the cellular environment.