The proposed research aims to address the gap between understanding and affecting disease by innovating in chemistry and exploring complex biology with small molecules. The research focuses on two pathways - electrophile stress-response pathways and chromatin-mediated gene regulatory pathways. These two pathways are fundamental to human disease biology, but remain poorly understood. The proposed research seeks to understand the selective interaction of subsets of electrophiles with the complex cell circuitry surrounding sulfur metabolites and how cellular electrophilic-stress response pathways might be modulated to develop new therapeutics. The proposed research also seeks to identify novel allosteric modulators of the polycomb repressive complex-2 (PRC2), the key mediator of epigenetic gene silencing, to illuminate novel cellular modes of regulation.

Public Health Relevance

The proposed research aims to address the gap between understanding and affecting disease by innovating in chemistry and exploring complex biology with small molecules. The research aims to discover small molecules that modulate two biological processes - stress signaling and chromatin signaling - with considerable promise for medicine. Such small molecules will be used to probe the consequences of modulating key mediators of the processes in order to gain a better understanding of the biology of these pathways and their medical potential as targets for novel therapeutics.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM038627-29
Application #
8759461
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
Project End
Budget Start
Budget End
Support Year
29
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Broad Institute, Inc.
Department
Type
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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Boskovic, Zarko V; Hussain, Mahmud M; Adams, Drew J et al. (2013) Synthesis of piperlogs and analysis of their effects on cells. Tetrahedron 69:
Schaefer, Giannina I; Perez, Jose R; Duvall, Jeremy R et al. (2013) Discovery of small-molecule modulators of the Sonic Hedgehog pathway. J Am Chem Soc 135:9675-80
Ignatenko, Vasily A; Han, Yong; Tochtrop, Gregory P (2013) Molecular library synthesis using complex substrates: expanding the framework of triterpenoids. J Org Chem 78:410-8
Yuan, Y; Tang, A J; Castoreno, A B et al. (2013) Gossypol and an HMT G9a inhibitor act in synergy to induce cell death in pancreatic cancer cells. Cell Death Dis 4:e690
Adams, Drew J; Boskovic, Zarko V; Theriault, Jimmy R et al. (2013) Discovery of small-molecule enhancers of reactive oxygen species that are nontoxic or cause genotype-selective cell death. ACS Chem Biol 8:923-9
Luo, Xuelai; Liu, Yongxiang; Kubicek, Stefan et al. (2011) A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases. J Am Chem Soc 133:9451-6
Kemp, Melissa M; Wang, Qiu; Fuller, Jason H et al. (2011) A novel HDAC inhibitor with a hydroxy-pyrimidine scaffold. Bioorg Med Chem Lett 21:4164-9
Shaw, Stanley Y; Blodgett, David M; Ma, Maggie S et al. (2011) Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes. Proc Natl Acad Sci U S A 108:492-7

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