25 Nov 2016, at REMER Talks, Hatice Karatas from Ecole Polytechnique Federale de Lausanne is going to be at REMER.
What about topic of seminar?
Protein-protein interactions represent, mainly unexplored, yet challenging opportunities to address unmet needs in therapy. MLL1 is a histone-3 lysine-4 (H3K4) methyltransferase, which is misregulated in patients with acute leukemia through upregulation of certain MLL1 target genes. The interaction of MLL1 with WDR5 is essential for its catalytic activity and therefore disruption of this protein-protein interaction may provide significant therapeutic benefit. In this project, starting from a 12-mer peptide, we have developed highly potent, cell permeable and metabolically stable small cyclic peptidomimetics, which were first-in-class inhibitors of MLL1. We have shown that these peptidomimetics can block the interaction between MLL1 and WDR5, reduce expression of MLL1 target genes and selectively inhibit growth of leukemia cell lines with MLL1 abnormalities. Our study showed that targeting MLL1 activity could be a novel approach for acute leukemia therapy.
When developing novel peptidic drugs for intracellular targets, assessment of efficacy to cross the cellular membrane is critical, as this class of compounds suffer from poor membrane permeability. However, the most frequently used methods to image cellular uptake of peptides rely on covalent attachment with a large hydrophobic imaging moiety that can influence the uptake properties and yield false positives. In order to address the need, we have developed a novel bioluminescent method, split luciferin peptide uptake (SLPU) assay, which uses the bioorthogonal reaction between D-Cysteine and CBT to yield D-luciferin. We have shown optimization and application of this highly sensitive and flexible assay that allows monitoring real-time cellular uptake of a number of peptides simultaneously, therefore it would be easily adapted to early drug discovery platforms.
My future research plans are aimed at exploring new therapeutic targets, including HoxA9, a transcription factor deregulated in acute leukemia. Inhibiting HoxA9 interaction with co-factors necessary for its activity has significant therapeutic potential. I will also develop novel imaging technologies (e.g. ligand-mediated receptor-internalization) that can be used to screen drug candidates, to investigate biological mechanisms as well as to identify novel therapeutic targets.
Who is Hacer Karatas, Phd.?
Hacer Karatas, PhD., received her B.Sc. degree in Pharmacy (Ankara University) and M.Sc in Pharmaceutical Chemistry (Ankara University) where she worked on the synthesis of benzimidazole derivatives as antimicrobial agents against multidrug-resistant bacteria. She moved to Ann Arbor, MI (USA) for her PhD study at the Department of Medicinal Chemistry, University of Michigan in 2006. Her Ph.D thesis focused on structure based design of peptidomimetic inhibitors of a protein-protein (MLL1-WDR5) interaction, a novel epigenetic target for leukemia therapy. After graduation, she continued her work in the same group for the development of small molecule and cyclic-peptidomimetic inhibitors of the MLL1-WDR5 interaction, as well as for the synthesis of bromodomain inhibitors. She joined a bio-imaging laboratory at EPFL (Switzerland) in 2013 as postdoctoral scientist where she has been developing novel assay technologies to monitor cellular uptake of molecules.