Design and synthesis of antagonists of BIR3 domain of X-linked Inhibitor of Apoptosis Protein
Hegab, Taher M.
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Resistance to chemotherapy is a major problem that faces the war against cancer. The mechanism of resistance has been widely studied and several mechanisms have been identified. One of the established mechanisms of resistance is through the inhibition of apoptosis (programmed cell death). The programming of normal cell is to undergo apoptosis if subjected to severe damage; some cancer cells avoid this fate by increasing the expression of the proteins that inhibit apoptosis. The Inhibitor of Apoptosis Proteins (IAP) is family of proteins that inhibit apoptosis and many of their members have been connected with resistance to chemo and radiotherapy. An important member of this family of proteins is the X-linked Inhibitor of Apoptosis Proteins (XIAP). This work describes the effort to discover a small molecule inhibitor of XIAP, using structure based design, synthesis of small focus libraries of compounds, and biological testing of these compounds. Nearly a hundred compounds have been synthesized and tested. Most of the compounds were tested in a fluorescence based NIH screen and showed no significant activity at a 50 μM concentration. The compounds are currently being tested against different cancer cell lines and initial results received showed that compound 111 , at concentration of 10 μM inhibited cell growth and induced morphological changes suggesting apoptosis in MCF-7 and MDA-MB-231 human breast cancer cell lines. Further testing is in progress.