Antagonism of the Oncogenic Bak–Bcl-xL and Bak–Mcl-1 Protein–Protein Interactions with Synthetic-Helix Mimetics
|Date(s)|| 03/04/2013 - 4:00 p.m.
|Location||Donahue Auditorium, Gordon Science Center|
|Presenter||Steven Fletcher, Ph.D., Assistant Professor, Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy|
|Description|| Abstract: Bcl-xL and Mcl-1 are anti-apoptotic proteins that are tightly regulated by pro-apoptotic proteins, which include Bak and Bim. The protein–protein interaction is mediated by an amphipathic a-helix referred to as the BH3 “death” domain, which is located on the pro-apoptotic proteins and is engaged by a hydrophobic crevice on the anti-apototic proteins. We have designed synthetic mimetics of the hydrophobic face of the Bak-BH3 a-helix and identified potent inhibitors of Bcl-xL and Mcl-1 in vitro (for example, JY-1-106: Kd = 196 nM (Bcl-xL), 10 mM (Mcl-1)). Furthermore, our compounds disrupt the Bak–Mcl-1 interaction in cells, and, through freeing up of the pro-apoptotic proteins, induce intrinsic apoptosis of Bcl-xL and Mcl-1 overexpressing cancer cell lines. Preliminary animal studies indicate our lead compound JY-1-106 exhibits good anti-tumor activity. Mcl-1 has recently emerged as a “hot” anti-cancer target since its overexpression results in resistance to conventional chemotherapeutic drugs. Current work involves developing more potent and more selective Mcl-1 inhibitors through mimicry of both the polar and hydrophobic faces of the BH3 a-helix, which will represent the first-ever functional, synthetic, amphipathic a-helix mimetics.
The Asa Gray Seminar Series is sponsored by the Asa Gray Biological Society, and is the longest running seminar series at Utica College. Scientists are invited from throughout the region to present seminars on their ongoing research.
All lectures are held in Donahue Auditorium, Gordon Science Center, at 4:00 p.m. An informal reception immediately follows. Call (315) 792-3028 for more information.
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