Winner: Biological Sciences (Graduate)
co-authors: James McCormick (co-first author), Chanyang Park, Courtney Follit, Jesiska Lowe, Pia Vogel, and John Wise.
https://youtu.be/urf3w7dgVoo
Abstract (click to view)
Multidrug resistance (MDR) describes the intrinsic or acquired resistance of cancers to diverse chemotherapeutics and is arguably one of most significant barriers to cancer treatment. As a mechanism of MDR, cancers commonly overexpress ATP-binding cassette transporters such as P-glycoprotein (P-gp). P-gp harnesses the power of ATP hydrolysis to efflux cytotoxic compounds across the cell membrane. Inhibition of P-gp can re-sensitize cancers to chemotherapeutics, but many P-gp inhibitors are also transport substrates of P-gp. Consequently, high compound dosages can be required to inhibit P-gp, and this can result in toxic off-target effects. To identify potential P-gp inhibitors that are not transport substrates, we iteratively screened millions of compounds against dynamic P-gp targets using massive parallel docking experiments. Hits from computational screens were then subjected to QSAR and purchased for testing. Compounds were assessed for their ability to reverse MDR using two sets of paired, human cancer cell lines – two chemotherapy resistant, P-gp overexpressing lines, and two chemotherapy-sensitive, non-P-gp overexpressing lines. Compounds were then tested for inherent toxicity against a non-cancerous human cell line. Lastly, we determined if our putative inhibitors are P-gp substrates using LC-MS/MS intracellular accumulation assays. We report a global hit rate of 15%.
Lauren Ammerman
Program: PhD in Biological Sciences
Faculty mentor: John Wise