SMERs: Small Molecule Enhancers for Treatment of Cancer and Neurodegenerative Diseases
Summary Background: Autophagy is the process by which cells cannibalize cellular elements such as proteins and organelles to generate intracellular metabolites for cell survival and cell death. For example, a cell undergoes autophagy for architectural remodeling during development or to eliminate damaging cytoplasmic components during oxidative stress, infection, or accumulation of protein aggregates. Many external factors play a role in regulating autophagy, the best characterized of which is the target of rapamycin (TOR) kinase, which negatively regulates the autophagy pathway in organisms from yeast to man. Studies have shown that inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Currently, the only confirmed pharmacological strategy for up-regulating autophagy in mammalian brains is treatment with rapamycin, a specific TOR inhibitor. As such, the modulation of autophagy and/or the TOR pathway with rapamycin may be useful in treating a wide range of diseases such as cancer and neurodegenerative diseases However, TOR controls several cellular processes besides autophagy and as a consequence contributes to long-complications, such as immunosuppression. Accordingly, safer ways of inducing autophagy are needed by identifying of new compounds that directly promote its effects.Invention: Novel small molecule enhancers of rapamycin (SMERs) that activate mammalian autophagy. A primary yeast-based screen was performed of over 2,000 compounds to identify compounds that induce the characteristic phenotype of autophagy (i.e. the accumulation of EGFP-LC3 positive autophagosomes in the cytoso). These small molecules enhance the clearance of mutant aggregate-prone proteins in both mammalian and Drosophila models of Huntington Disease as well as models of spinocerebellar ataxia type 3 and Parkinsons disease. The SMERs represent eleven distinct structural classes and promote autophagy with an EC50 as low as 1.4 uM.
In one example demonstrating the efficacy of SMERs in reducing aggregation of the Huntington protein mutant (HDQ74) in a Huntington Disease model, SMERs were tested on autophagy-competent (Atg5 Wildtype) mouse embryonic fibroblasts (MEFs) or matched MEFs (Atg5 Knockout) lacking the essential autophagy gene Atg5. HDQ74 aggregation was significantly increased in untreated autophagy-deficient cells compared to untreated wild type cells. When these cells were treated with SMERs the HDQ74 aggregation was significantly reduced in wild type cells, but not in knockout cells.
Applications Advantages: The SMERs can be used to design better modulators of autophagy or to better understand the autophagy-lysosome pathway in cells. The overall enhancement profile of SMERs was neither strain nor species specific, as all tested SMERs exhibited comparable activity in other S. cerevisiae strains as well as in laboratory strains of Saccharomyces bayanus, Saccharomyces mikatae, and Saccharomyces paradoxus. SMERs modulate autophagy, in part, by affecting acetylation/deacetylation activity in the cell, such as by histone deacetylase 6 activity. SMERs and rapamycin have an additive effect on the clearance of mutant aggregate-prone proteins in mammalian cells. SMERs induce autophagy independently of rapamycin in mammalian cells.
Applications: SMERS are to be used to treat diseases such as cancer, inflammatory diseases, autoimmune diseases, neurodegenerative diseases (e.g., Alzheimers disease, Parkinsons disease), infectious diseases, cardiovascular diseases, or any diseases caused by protein misfolding and/or mishandling. SMERs can be combined with other pharmaceutical agents to provide combination therapies, for example, proteasome inhibition, kinase, and growth factor pathway inhibition. For example, after growth factor withdrawal, cancer cells in tissue culture have been found to undergo autophagy to remain alive. Therefore, the inhibition of autophagy and the inhibition of growth factor pathways would provide synergistic toxicity and a novel approach to treat cancer.
Publications: Sarkar S, Perlstein EO et al. Small molecules enhance autophagy and reduce toxicity in Huntington's disease models Nat Chem Biol. 2007 Jun;3(6):331-8. For Further Information Please Contact the Director of Business Development Laura Brass Email: [email protected] Telephone: (617) 495-3067
Inventor(s): Schreiber, Stuart L.
Type of Offer: Licensing
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