2016 Development Grants
Developing a ubiquitin-dependent proteasome activity reporter
Developing a ubiquitin-dependent proteasome activity reporter to screen for activators and inhibitors
Ying Lu and Marc Kirschner
The 26S proteasome mediates both ubiquitin-dependent and ubiquitin-independent protein degradation and plays critical roles in the immune response, stress response and gene regulation. Current proteasome inhibitors, targeting only the rather nonspecific core particle, have nevertheless shown efficacy in cancer but they indiscriminately affect most functions of the proteasomes. With the help of Q-FASTR grant, we have successfully invented a novel and powerful screening platform for testing inhibitors that distinguish between ubiquitin-dependent and independent activities. We have performed initial screening and identified novel inhibitors with such specificity. By precisely modulating selected activities of the proteasome, these new classes of inhibitors could advance the treatment of cancer, inflammation and neurodegenerative disease. Currently, we are looking for partners to bring the project to the next phase.
Restoring Cortical Function and Plasticity Treatment of AD
Restoring Cortical Function and Plasticity for the Treatment of Alzheimer’s Disease
Brian Chow, Adam Granger, Sarah Melzer, and Bernardo Sabatini
Alzheimer’s disease (AD)is characterized by degeneration and dysfunction of the brain. In particular, a large folded expanse of the brain known as cortex is severely affected. Treatments for AD can aim at either stopping the degeneration or at maximizing the function of the remaining cortex. Here we proposed a new approach for the latter. We proposed to manipulate a specific cell type in cortex, known as VIP cells, which have the ability to regulate cortical function, plasticity, and blood flow. We have identified a molecular regulator that is uniquely expressed in VIP cells that provides a means to control these cells, and thereby cortex. We have been working to characterize the regulation of cortex by this pathway and establish it as a preclinical model for the enhancement of cortical function. If our hypotheses are correct, we will have identified a druggable pathway to enhance cognitive function in disease states
Targeted protein degradation as a strategy for potent antivirals
Assessment of targeted protein degradation as a strategy for potent antivirals with high barriers to resistance
Mélissanne de Wispelaere, Deirdre Costello, Tinghu Zhang, Guangyan Du, Nathaniel J. Henning, Supanee Potisopon, Eric S. Fischer, Radoslaw Nowak, Matthew Ponthier, Bethany Berry, Nathanael S. Gray, Priscilla L. Yang
There is a major need for antivirals to combat the diverse viral pathogens causing human disease. Drugs that potently inhibit one or more related viruses with high natural barriers to resistance remain a much-desired but elusive goal. “Degronimids” represent a new class of inhibitors that induce degradation of their targets through recruitment of the E3 ubiquitin ligase cereblon. This inhibitory strategy can alleviate the need for stoichiometric target engagement and also suppress drug resistance. Recent examples in cancer biology demonstrate that degronimids against kinases and transcriptional enzymes deplete their requisite targets and have superior efficacy and resistance profiles relative to the parental compounds. Here, we propose to develop and evaluate degronimids that inhibit hepatitis C virus and dengue virus through inhibition and targeted degradation of specific viral targets. The goal of this work is to provide proof of concept that degronimid antivirals have superior antiviral potency and resistance profile when compared to the parental compounds. Viral targets and parent inhibitors have been judiciously selected to allow synthesis and characterization of antiviral degronimids on a relatively short time scale by leveraging our virological tools and expertise as well as by taking advantage of resistance mutations that have already been well-documented in the literature
2016 Pilot Grants
Building Better Screens and Identifying Ligands for Human MS4A
Building Better Screens and Identifying Ligands for Human MS4A proteins
Maria Lissitsinya Bloom, Talya Kassessian, and Sandeep Robert Datta
In the nose, a family of proteins called the MS4As act as small molecule detectors. These receptors detect ethologically relevant molecules from the environment, including nitrogenous heterocyclics and long chain fatty acids. The MS4As have been strongly implicated by human genetic studies in the development of Alzheimer’s Disease, although the mechanism through which the MS4As are linked to disease are completely unknown. The MS4As are expressed within microglia, a chemosensory cell type within the brain that have been associated with AD progression. We hypothesize that the ability of the MS4As to detect endogenous ligands found in the brain might mediate neuroinflammation associated with AD; if true, this suggests that the MS4As might define a completely new molecular mechanism underlying the AD progression. However, a major challenge in de-orphanizing the MS4As and in identifying chemical activators and inhibitors is the poor behavior of these receptors when expressed on their own in typical reconstitution systems like HEK cells. With support from Q-FASTR, we screened through a variety of cell lines and tested several chaperone candidates, in an attempt to convert our single cell screen for MS4A-dependent responses into a platform useful for high-throughput screening. This work continues, in the hope that identified ligands will be important starting templates for the development of molecules that manipulate MS4A activity, which may have significant therapeutic potential for treating AD.
Microtubule stabilizing drugs-neurodegenerative disease and SCI
Microtubule stabilizing drugs for neurodegenerative disease and spinal cord injury
Yuyu Song and Timothy Mitchison
Our 3-5 year goal is to develop small molecules drugs for neurodegenerative diseases and/or spinal cord injury that bind directly to microtubules and stabilize them in CNS neurons and glia. This well-defined pharmacological mechanism protects neurons from degenerative pathologies, and promotes axon growth in damaged spinal cord. It showed considerable promise in rodent models of neurodegeneration, spinal cord injury and schizophrenia using epothilone-D and -B as CNS-penetrating tool compounds. The potential efficacy of epothilones in man is limited by high peripheral toxicity. They kill dividing cells by stabilizing mitotic spindle microtubules and were originally developed as cytotoxic cancer drugs, making them a poor starting point for neurology drugs, despite their promising mechanism. To develop fundamentally less toxic microtubule stabilizing drugs that retain neuro-protective and neuro–regenerative activities we will adopt approaches from GPCR pharmacology that have never been applied to microtubule drugs. We will use ligand displacement assays as our primary screen, and then evaluate neuroprotective, cytotoxic and microtubule stabilizing activities in follow-up assays. In a 1-year pilot we propose to test the concept that we can obtain scaffolds which bind to the epothilone site and exhibit superior neuroprotective to cytotoxic ratios compared to current tool compounds. If we validate this concept, we will pursue a drug development project based using the assays and concepts we develop during the pilot phase.