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|Title:||IDENTIFICATION AND CHARACTERIZATION OF SMALL MOLECULE MODULATORS OF BCL-2 FAMILY PROTEINS|
|Department:||Biochemistry and Biomedical Sciences|
|Abstract:||Apoptosis is a tightly regulated form of cell death fundamental to multi-cellular organisms for maintaining cellular homeostasis and removing damaged or dangerous cells. Disruptions in the apoptotic pathway that result in excessive or insufficient apoptosis are associated with many conditions including cancer, auto-immune diseases and neurodegenerative diseases. The Bcl-2 family proteins are the central regulators and executors of apoptotic signals at the mitochondrial outer membrane (MOM). Permeabilization of the MOM by the Bcl-2 family proteins, Bax and Bak, marks commitment to death and is considered to be the point of no return for most cells. Therefore, restoring normal apoptosis by targeting the Bcl-2 family proteins represents a potentially important avenue for novel therapeutics. Small molecules targeting Bcl-2 family proteins are important for mechanistic studies and serve as potential leads for novel therapeutics. The findings presented in this thesis were focused on identifying and characterizing small molecules that promote or inhibit Bax and/or Bak mediated MOM permeabilization. Four small molecules, MSN-50, MSN-125, OICR766A and SRI-O13 were identified by screening compound libraries for molecules that inhibit or promote Bax mediated permeabilization. MSN-50 and MSN-125 inhibit Bax and Bak mediated membrane permeabilization and confer protection of cells against apoptotic stimuli. The compounds inhibit Bax mediated MOMP by disrupting partial, but not all, interfaces of the Bax dimer. OICR766A activates Bax by a mechanism distinct from activator BH3 proteins and cysteine 126 of Bax is required for activation by this compound. SRI-O13 enhances Bax and Bak mediated MOM permeabilization and displays anti-tumor activity in mice. Additionally, SRI-O13 synergizes with various apoptosis inducing agents to promote MOM permeabilization. Taken together, this work has increased the understanding of the mechanisms and interactions of Bcl-2 family proteins highlights the benefits of pharmacologically targeting Bcl-2 family proteins.|
|Appears in Collections:||Open Access Dissertations and Theses|
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|Brahmbhatt_Hetal_2016March_PhD.pdf||5.28 MB||Adobe PDF||View/Open|
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