BEGIN:VCALENDAR VERSION:2.0 PRODID:-//jEvents 2.0 for Joomla//EN CALSCALE:GREGORIAN METHOD:PUBLISH BEGIN:VEVENT UID:b359eb8ba1d3b327c1fc006b6852e93c CATEGORIES:Colloquium CREATED:20170816T175000 SUMMARY:Fall 2017 Colloquium: Professor John Karanicolas DESCRIPTION:
Tuesday September 1 9, 2017
Wright-Reiman Labs Room 260
"Computational Chemical Biology to Address Non-traditiona l Drug Targets"
Decades of research efforts, expedited in recent year s by next-generation sequencing technologies, have carefully cataloged recu rrent 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, rath er than established targets such as kinases and GPCRs. I will describe ongo ing efforts in my lab two address two such target classes: RNA-binding prot eins 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 d esigning small-molecule inhibitors. With this approach we first target Musa shi-1, a stem cell marker that is upregulated in many cancers. We design an d synthesize novel inhibitors that are active in biochemical and cell-based assays against Musashi-1, and then demonstrate how these inhibitors can al so 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 muta ted or deleted in more than half of human cancers. The most frequently occu rring of these loss-of-function mutations are localized to the p53 “core do main,” but do not involve surface residues directly responsible for functio n. Rather, these point mutants reduce the thermodynamic stability of this m arginally 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 intera ct with this surface. Through biochemical assays we find that these compoun ds are effective at stabilizing multiple different p53 mutants. We further find that these compounds can restore transcriptional activity in cell line s 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 occu rring class of p53 point mutants.
Together these two vignettes highli ght the potential druggability of many “non-traditional” target classes, ex pending the scope of potential avenues for therapeutic intervention.
~Coffee/tea will be served prior to lecture.~
X-ALT-DESC;FMTTYPE=text/html:Tuesday September 19, 2017
Wright-Reiman La bs Room 260
"Computational Chemical Biolo gy to Address Non-traditional Drug Targets"
Decades of research effor ts, expedited in recent years by next-generation sequencing technologies, h ave carefully cataloged recurrent driver gene mutations in many different c ancers. A somewhat dismaying insight from these studies is the observation that the underlying genetic alterations in cancer are dominated by “new” po tential target classes, rather than established targets such as kinases and GPCRs. I will describe ongoing efforts in my lab two address two such targ et classes: RNA-binding proteins and destabilized tumor suppressors.
I will begin by focusing on RNA-binding proteins (RBPs) that are key regula tors of post-transcriptional gene expression, and underlie many processes w ith cancer relevance. I will describe a strategy that entails extracting a “hotspot pharmacophore” from the structure of a protein-RNA complex, and us ing this as a template for designing small-molecule inhibitors. With this a pproach we first target Musashi-1, a stem cell marker that is upregulated i n many cancers. We design and synthesize novel inhibitors that are active i n biochemical and cell-based assays against Musashi-1, and then demonstrate how these inhibitors can also be used as tool compounds to probe the activ ity of close homolog Musashi-2.
Next, I will turn to p53, a tumor sup pressor protein that is mutated or deleted in more than half of human cance rs. The most frequently occurring of these loss-of-function mutations are l ocalized to the p53 “core domain,” but do not involve surface residues dire ctly responsible for function. Rather, these point mutants reduce the therm odynamic stability of this marginally stable protein, such that cellular ac tivity is diminished because an insufficient amount of p53 is correctly fol ded. 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 assay s we find that these compounds are effective at stabilizing multiple differ ent p53 mutants. We further find that these compounds can restore transcrip tional activity in cell lines harboring destabilized mutants of p53, withou t 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.
Togethe r these two vignettes highlight the potential druggability of many “non-tra ditional” target classes, expending the scope of potential avenues for ther apeutic intervention.
~Coffee/tea will be served prior to lec ture.~
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