Dibenzophenanthridines as inhibitors of phosphate-activated glutaminase C and cancer cell proliferation
Menée in vitro, cette étude évalue les effets d'une petite molécule, une dibenzophénanthridine inhibitrice d'une enzyme du métabolisme, la glutaminase C, sur la prolifération de cellules de cancer du sein
One of the hallmarks of cancer cells is their adaptation to rely upon an altered metabolic scheme that includes changes in the glycolytic pathway, known as the Warburg effect, and elevated glutamine metabolism. As a consequence of these metabolic changes, cancer cells are often described as being addicted to glutamine. Glutaminase, a mitochondrial enzyme, plays a key role in the metabolism of glutamine in cancer cells, and thus its inhibition could significantly impact malignant transformation. The small molecule 968, a dibenzophenanthridine, was recently shown to be an inhibitor of recombinantly expressed glutaminase C, to block the proliferation and anchorage independent colony formation of human cancer cells in culture, and to inhibit tumor formation in mouse xenograft models. Here, we examine the structure-activity relationship and binding mode that leads to 968-based inhibition of glutaminase and cancer cell proliferation, focusing in particular upon a 'hot-spot' ring previously identified to be critical to 968 activity. We find that the hot-spot ring must be substituted with a large, non-planar functionality (e.g. a t-butyl group) in order to bestow activity to the series, leading us to a model whereby the molecule binds glutaminase at a previously undescribed allosteric site. Using this information, we conduct docking studies to locate potential 968-binding sites, and proceed to test a specific set of docking solutions via site-directed mutagenesis. Moreover, we verify the results from our initial assay of 968 and its analogues by cellular studies using MDA-MB-231 breast cancer cells.
http://mct.aacrjournals.org/content/early/2012/04/10/1535-7163.MCT-11-0942.abstract