Title: Targeting IAPs as An Approach to Anti-Cancer Therapy
Volume: 11
Issue: 3
Author(s): Christopher S. Straub
Affiliation:
Keywords:
Apoptosis, IAP antagonists, XIAP, cIAP, Smac/DIABLO, caspase, peptidomimetics, IAPs, Anti-Cancer Therapy, immune system, homeostasis, neurodegeneration, cancer, programmed cell death, tumor suppressor genes, anti-apoptotic factors, Bcl-2, Apoptosis Proteins (IAP), receptor-ligand interactions, Cytochrome C, Apoptosome, Apaf1, Apollon, melanoma inhibitor, Survivin, E3 ubiquitin ligase activity, Caspase Recruitment Domain, BIR3 domain, IAP binding motif, Tumor Necrosis Factor, Drosophila, human cancer, NMR, X-ray crystallography, Tyr324, Lys297, dimethylglycine, cyclopropylglycine, Proline, Phenylalanine, ALANINE MIMETICS, VALINE MIMETICS, AVPX LEAD, Embelin, Bestatin, SKOV3
Abstract: Apoptosis is an essential process for embryonic and lymphocyte development, immune system modulation and tissue homeostasis. Defects in apoptotic signaling often lead to diseases of immune deficiency, neurodegeneration and cancer [1,2]. In the cancer arena, these defects may contribute to the establishment and growth of tumors. Moreover, many cytotoxic chemotherapies act in part by activating these apoptotic networks. Occasionally apoptotic pathways are activated, however key players downstream of initiation are inhibited by negative regulators that have been dysregulated by the diseased state of the cell. Removal of these barriers to apoptosis signaling, it has been rationalized, could restore cell death in diseased cells while sparing those that are not primed for programmed cell death. Additionally, the subversion of these death evading mechanisms may re-sensitize cells that have developed resistance to chemotherapies in this manner. The importance of apoptosis as a maintenance process, and the promise that restoring this signaling could mean in treating cancer has placed many targets on the front line of oncology research. Approaches are being developed that will activate death receptor pathways, synthetically activate caspases, restore the activity of tumor suppressor genes such as p53, and counteract the effects of anti-apoptotic factors. Among these approaches, small molecules are in clinical trials against several anti-apoptotic players, namely the Bcl-2 and IAP proteins. This review will focus on the efforts being advanced against the Inhibitor of Apoptosis Proteins (IAP), the chemical matter of the inhibitors and the biology emerging from this research.
