Tuesday September 19, 2017
Wright-Reiman Labs Room 260
"Computational Chemical Biology to Address Non-traditional Drug Targets"
Decades of research efforts, expedited in recent years by next-generation sequencing technologies, have carefully cataloged recurrent driver gene mutations in many different cancers. A somewhat dismaying insight from these studies is the observation that the underlying genetic alterations in cancer are dominated by “new” potential target classes, rather than established targets such as kinases and GPCRs. I will describe ongoing efforts in my lab two address two such target classes: RNA-binding proteins and destabilized tumor suppressors.
I will begin by focusing on RNA-binding proteins (RBPs) that are key regulators of post-transcriptional gene expression, and underlie many processes with cancer relevance. I will describe a strategy that entails extracting a “hotspot pharmacophore” from the structure of a protein-RNA complex, and using this as a template for designing small-molecule inhibitors. With this approach we first target Musashi-1, a stem cell marker that is upregulated in many cancers. We design and synthesize novel inhibitors that are active in biochemical and cell-based assays against Musashi-1, and then demonstrate how these inhibitors can also be used as tool compounds to probe the activity of close homolog Musashi-2.
Next, I will turn to p53, a tumor suppressor protein that is mutated or deleted in more than half of human cancers. The most frequently occurring of these loss-of-function mutations are localized to the p53 “core domain,” but do not involve surface residues directly responsible for function. Rather, these point mutants reduce the thermodynamic stability of this marginally stable protein, such that cellular activity is diminished because an insufficient amount of p53 is correctly folded. Using new computational tools developed in my lab, we have discovered a new druggable site on the surface of the p53 core domain, and identified compounds designed to interact with this surface. Through biochemical assays we find that these compounds are effective at stabilizing multiple different p53 mutants. We further find that these compounds can restore transcriptional activity in cell lines harboring destabilized mutants of p53, without affecting cells that have wild-type p53. We suggest that these compounds bind and stabilize correctly folded p53, allowing them to restore activity to this most frequently occurring class of p53 point mutants.
Together these two vignettes highlight the potential druggability of many “non-traditional” target classes, expending the scope of potential avenues for therapeutic intervention.
~Coffee/tea will be served prior to lecture.~