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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Fabian, Miles
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Broad Institute, Inc.
United States
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Nelson Jr, Shawn D; Wawer, Mathias J; Schreiber, Stuart L (2016) Divergent Synthesis and Real-Time Biological Annotation of Optically Active Tetrahydrocyclopenta[c]pyranone Derivatives. Org Lett 18:6280-6283
Hideshima, Teru; Qi, Jun; Paranal, Ronald M et al. (2016) Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma. Proc Natl Acad Sci U S A 113:13162-13167
Wagner, Bridget K; Schreiber, Stuart L (2016) The Power of Sophisticated Phenotypic Screening and Modern Mechanism-of-Action Methods. Cell Chem Biol 23:3-9
Gerry, Christopher J; Hua, Bruce K; Wawer, Mathias J et al. (2016) Real-Time Biological Annotation of Synthetic Compounds. J Am Chem Soc 138:8920-7
Chattopadhyay, Shrikanta; Stewart, Alison L; Mukherjee, Siddhartha et al. (2015) Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors. Cell Rep :
Scully, Stephen S; Zheng, Shao-Liang; Wagner, Bridget K et al. (2015) Synthesis of oxazocenones via gold(I)-catalyzed 8-endo-dig hydroalkoxylation of alkynamides. Org Lett 17:418-21
Iaconelli, Jonathan; Huang, Joanne H; Berkovitch, Shaunna S et al. (2015) HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells. ACS Chem Biol 10:883-90
Abazeed, Mohamed E; Adams, Drew J; Hurov, Kristen E et al. (2013) Integrative radiogenomic profiling of squamous cell lung cancer. Cancer Res 73:6289-98
Schaefer, Giannina I; Perez, José R; Duvall, Jeremy R et al. (2013) Discovery of small-molecule modulators of the Sonic Hedgehog pathway. J Am Chem Soc 135:9675-80
Yuan, Yuan; Hartland, Kate; Boskovic, Zarko et al. (2013) A small-molecule inducer of PDX1 expression identified by high-throughput screening. Chem Biol 20:1513-22

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