Teva Pharmaceuticals Marc A. Goshko Memorial Grant Program Awardees 2015 - 2018
Dr. Amy M. Barrios
University of Utah
“A Unified Approach to the Development of Protein Tyrosine Phosphatase Targeted Chemical Probes.”
Tyrosine phosphorylation and dephosphorylation control all aspects of cell signaling from differentiation to the immune response. Misregulation of tyrosine phosphorylation has been implicated in numerous disease states including cancer, diabetes and autoimmunity. The enzymes that control tyrosine phosphorylation in vivo, the protein tyrosine kinases (PTKs), have been well-studied; their roles in several key cellular signaling pathways are known and PTK inhibitors have been successful in the clinic. While much less is known about the enzymes that control tyrosine dephosphorylation, there is ample evidence that these protein tyrosine phosphatases (PTPs) also play critical roles in cellular signaling. In addition, the PTPs are promising but recalcitrant therapeutic targets. However, the dearth of chemical tools available for studying PTP activity in cells and in vivo has impeded progress in the field. My laboratory aims to restore balance to our understanding of PTP and PTK mediated cell signaling by providing a toolkit of PTP-targeted substrates and inhibitors. To date, the PTP-selective, fluorogenic substrates developed in our lab have illuminated the cellular activity of PTPs and facilitated single cell inhibitor screening, while the potent, selective PTP inhibitors identified by our lab have helped to validate the lymphoid tyrosine phosphatase (LYP) as a promising therapeutic target for the treatment of anaphylaxis. Thanks to the generous support provided by Teva Pharmaceuticals, we will now be able to take this project to the next level: developing a unified approach to PTP-selective substrate and inhibitor design and providing the toolkit necessary to elucidate the biological roles of the PTPs in health and disease.
Dr. Ryan Looper
University of Utah
“Repurposing Old Scaffolds as New Anti-Tubercular Leads.”
While the incidence of tuberculosis (TB) has steeply declined in the U.S., it remains one of the world’s deadliest diseases. Despite this pressing global health crisis, no new TB drug has been developed in almost 50 years and the current curative regimens require lengthy treatment, complicated administration and can be toxic at the doses needed to treat emerging strains of multi-drug and extensively-drug resistant Mycobacterium tuberculosis (Mtb). TB / HIV co-infection is considerably distressing as most common TB drugs (e.g. rifampin) are strong activators of hepatic cytochromes, rendering highly active anti-retroviral therapy (HAART) used to treat HIV ineffective. The goals of this proposal integrate synthetic and medicinal chemistry, microbiology and structural biology to 1) explore a newly identified antibiotic scaffold that acts by inhibiting ribosomal protein synthesis and is compatible with HAART; 2) shorten TB treatment regimens by disrupting mycobacterial biofilm physiology and 3) evaluate these treatments ability to incur resistance.
Dr. Tehshik Yoon
University of Wisconsin-Madison
“Practical Photochemical Synthesis: Enabling Exploration of Unchartered Chemical Space.”
The Yoon laboratory is interested in synthetic organic photochemistry and the opportunities photochemical synthesis offers for the construction of unique, structurally complex small molecules. A central theme of our research is the design of photocatalytic systems that utilize long-wavelength, low-energy visible light. These methods provide better functional group compatability, greater operational convenience, and superior stereocontrol compared to direct UV photochemistry. The goal of the research funded by the Teva grant is to apply the photocatalytic methodology developed in our laboratory to the synthesis of stereochemically well defined and densely functionalized cyclobutane building blocks that are directly applicable to the synthesis of novel bioactive small molecules. We will demonstrate the flexibility of this strategy by applying it to the synthesis of a large family of cyclobutane-containing natural products. This generous award will enable us to begin translating our mechanistically inspired, fundamental research in photocatalytic synthesis to applications with real-world consequences.