INSTITUTO ARGENTINO DE MATEMATICA ALBERTO CALDERON
Unidad Ejecutora - UE
congresos y reuniones científicas
Translational Ideas in Molecular Cancer Therapy: Re-engineering kinase inhibitors to reduce their side effects
Congreso; Protein & Peptide Conference Pep Con 2011- BIT Life Sciences 4th Annual Protein & Peptide Conference, Beijing, China; 2011
ARIEL FERNANDEZ CHAIR SECTION 5-6: PROTEIN KINASE INHIBITORS IN CANCER. I shall present on current research endeavors in my research group focusing on controlling specificity in molecularly targeted anticancer therapy. A basic goal is to reduce toxic side effects by structure-based drug design exploiting our understanding of the molecular basis of specificity. Particular emphasis will be placed on engineering kinase inhibitors (KIs) with minimal clinical uncertainty. A radical innovation is on its way in terms of rationally redesigning KIs to reduce their toxicity: as it turns out, we can now control specificity to an unprecedented degree and hence decisively contribute to test the limits of therapeutic efficacy for KIs. To support this claim, I shall start by noting that cross reactivities of KIs arise because of the structural similarity and amino acid conservation across evolutionarily related (paralog) kinases. Yet, while paralogs share a similar structure, they are packed differently. If we compare the microenvironments of intramolecular hydrogen bonds aligned across paralog structures we shall notice crucial differences: some hydrogen bonds are exposed to solvent in one kinase and shielded from water in another, or, rather, one hydrogen bond may be deficiently packed in one kinase but well packed in another. Taking into account such local differences, we are able to redesign KIs because deficiently packed hydrogen bonds ?the so-called dehydrons - not only distinguish paralogs but are also sticky and hence targettable. Hence, a new design strategy to achieve higher specificity emerges as we redesign KIs to turn them into protectors (?wrappers?) of dehydrons that are not conserved across paralogs. Such wrapping designs enable paralog discrimination and hence lead to drugs with controlled specificity and capable of curbing side effects almost á la carte. Guided by the novel selectivity filter, we shall report on re-workings of major anticancer drugs like sunitinib and imatinib geared at suppressing their cardiotoxicity. Biography: Ariel Fernández received his Ph. D. in Physical Chemistry from Yale University in 1984 (fastest awarded doctorate in Yale history). He holds the Hasselmann Professorship in Bioengineering at Rice University and currently conducts research as Visiting Professor at the University of Chicago. Fernández has published over 300 papers, spanning a vast terrain of scientific knowledge from abstract algebra to molecular evolution, from molecular biophysics to clinical kinomics. His wrapping concept enabled Fernández to elucidate the molecular basis of drug specificity, a topic widely described in his recent book ?Transformative Concepts for Drug Design: Target Wrapping? (Springer, 2010).