Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM038627-32
Application #
9283557
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
1988-09-01
Project End
2018-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
32
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
02142

  Publications

Viswanathan, Vasanthi S; Ryan, Matthew J; Dhruv, Harshil D et al. (2017) Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547:453-457
Leshchiner, Elizaveta S; Rush, Jason S; Durney, Michael A et al. (2017) Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease. Proc Natl Acad Sci U S A 114:11392-11397
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
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
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
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
Boskovic, Zarko V; Kemp, Melissa M; Freedy, Allyson M et al. (2016) Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile. ACS Chem Biol 11:1844-51
Haftchenary, Sina; Nelson Jr, Shawn D; Furst, Laura et al. (2016) Efficient Routes to a Diverse Array of Amino Alcohol-Derived Chiral Fragments. ACS Comb Sci 18:569-74
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

Showing the most recent 10 out of 102 publications