Small Molecule De-Repression of BAX and BAK Oligomerization as a Strategy for Treating Cancer
Dean A. Fennell.
Overcoming chemotherapy and radiation resistance presents one of the greatest obstacles to improving clinical outcome for the majority of solid cancers. Chemotherapy and radiotherapy owe their clinical efficacy to their ability to kill cancer cells. A significant body of evidence has established programmed cell death, or apoptosis, as a final common pathway by which these modalities mediate cancer cell kill. The multi-domain BCL-2 family proapoptotic proteins BAX and BAK are critical regulators of mitochondrial outer membrane permeability (MOMP), a switch that irreversibly pushes cells into apoptosis. Several cancers commonly express at least one or more antiapoptotic BCL-2 family members, capable of arresting BAX and BAK activation. These proteins are now targets for a new generation of small molecule inhibitors that have the potential to mediate apoptosis sensitisation and therefore reverse clinical drug resistance. Development of several small molecule mimics of the BH3 domain has been based on a variety of methods including molecular modelling, ligand mimicry, natural library screening and perhaps most successfully, synthetic library screening. Novel BH3 mimetics with BAX BAK derepressing activity are now entering the clinic and may provide real opportunities for improving the efficacy of current therapy. This review focuses on small molecule inhibitors of the BCL-2 family proteins and their potential application in cancer therapies.
Keywords: CASP9, BCL-2 family proteins, antiapoptotic, Tetrocarcin A, Chelerythrine, ABT-737
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