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Drug Discovery, the effort to find new experimental drugs for treatment of disease, is the main focus of research in the Hansen Lab. We use both phenotypic screening and computational docking studies to identify small molecules with biological activity, then optimize those compounds for potency and pharmacology that support in vivo experimentation.
Ongoing projects with active lead molecules include (updated February 2019):
- CRL4 inhibitors for treatment of cancer and neurofibromatosis
- An ATP site-binding AMPK agonist for treatment of metabolic disease
- Natural product inhibitors of tryptase for treatment of skin inflammation
The first clinical candidate to emerge from our group is a novel microtubule polymerization inhibitor (Siddiqui-Jain et al., 2017; Siddiqui-Jain et al., 2018). Our lab contributed to the initial identification and preclinical proof of concept for this compound, including highlighting its novel pharmacology. The importance of this compound is that it is orally available, evades PGP, and overcomes resistance to approved microtubule targeting agents. This drug is being advanced into clinical trials in gastric cancer by Frost Biologic. Historically, our drug discovery emphasis arose out of our chemical biology research.
We use small molecules to understand epithelial cell biology. In our earliest work, we conducted a phenotypic screen designed to identify compounds that blocked HGF-induced epithelial-mesenchymal transition, then reveal control of that process by identifying the molecular targets of those compounds (Langford et al., 2012; Hoj et al., 2016). This work implicates TRP family calcium channels in epithelial rearrangements in development and disease. Our working model is that initiation of epithelial tissue rearrangements requires the delivery of TRP channels to the plasma membrane via microtubule-based trafficking and that calcium activates both cellular mechanics (Haws et al., 2016) and gene transcription programs. Our ongoing work uses small molecules to probe the role of TRP channels in epithelial morphogenesis during development, a collaboration with Dr Mike Stark.
Our cell biology interests are cytoskeletal system, cell-cell adhesion systems, and epithelial tissue remodeling. Our initial work was studying zyxin and its relative, LPP. We showed that zyxin mediates actin-membrane linkages at cell-cell contacts (Sperry et al., 2010), how zyxin is recruited to cell-cell junctions (Call et al., 2011), how zyxin- and LPP-VASP complexes alter actin dynamics (Moody et al., 2009; Grange et al., 2013), and how activity of zyxin-VASP complexes is controlled (Call et al., 2011; Thomson et al., 2011).
This work led us to efforts dissecting epithelial tissue remodeling more broadly using MDCK cell stimulated with HGF (scatter factor) as a model system. We showed interplay between different growth factor pathways in controlling epithelial scattering in this model (Chung et al., 2011) and characterized how cellular mechanics drive epithelial cell-cell detachment (Hoj et al., 2014). We remain interested in defining cellular control of actin-based mechanical forces during epithelia rearrangements.
Our ab is active in using multiple computational approaches in our overall research goals. Dr Hansen spent a year-long sabbatical in the Theoretical Systems Biology Group at Imperial College London in 2012-2013 to work with the research group of Dr. Michael Stumpf, specifically to learn about using computational approaches to addressing biological questions. We have published mathematical modeling of cancer progression (MacLean et al., 2014) and use of cellular automata to analyze cellular mechanics during epithelial cell-cell detachment – an extension of our cell biology focus, (Schmutz et al., 2017). We also employ bioinformatics approaches in a number of areas and use computational docking algorithms for computer aided drug design.
BIOACTIVE NATURAL PRODUCTS
Our work with natural product is an extension of our drug discovery efforts. Here we look to identify natural products and demonstrate their pharmacologic activity, allowing them to be used as leads in drug discovery or developing them as alternatives to existing synthetic drugs. We have done work with antiviral compounds (Cryer et al., 2017) that have been licensed for commercial development by KP Biosciences. Our ongoing work with natural products is listed in the drug discovery section.