EDUCATION

Cambridge, MA • 1999-2004

Ph.D., Chemistry (Organic Chemistry/Chemical Biology)

• Thesis: Discovery of Small Molecule Probes for Chemical Genetics Using Biased and Unbiased Diversity-Oriented Organic Synthesis.
• Key achievements included: discovery of the first paralog- and domain-selective inhibitor of histone deacetylase 6 (HDAC6), synthesis and biological evaluation of two highly enantio-enriched libraries of 1,3-dioxanes containing over 30,000 unique molecules in total
• Research Advisor: Professor Stuart L. Schreiber

Cambridge, MA • 1995-1999

B.S., Chemistry; minor in Music Performance

• Research projects included: synthesis of a key intermediate in an annulation approach toward the total synthesis of mitomycin C, studies on intramolecular [4+2] cycloadditions of alkyliminoacetonitriles
• Cumulative GPA: 5.0/5.0
• Undergraduate Research Advisor: Professor Rick L. Danheiser

Oberlin, OH • 2004-2005

• Taught lecture and laboratory courses in introductory and intermediate organic chemistry as well as a nonmajors’ course in basic chemistry
• Supervised two senior honors research projects in synthetic organic chemistry

Cambridge, MA • 2001-2004

• Led sections in organic chemistry and chemical biology for majors and non-majors in a 400–student undergraduate community.  Advised students applying to graduate school.   Provided writing advice on student applications for graduate school fellowships.

Cambridge, MA • 2002-2003

• Directed an undergraduate research project involving enantioselective synthesis and structure-activity-relationship (SAR) studies that contributed to a publication in the Journal of the American Chemical Society.

RESEARCH SUMMARY

I.        Synthesis, Screening, and Application of a Library of 7200 Enantiopure Molecules Biased Toward the Histone Deacetylases (HDACs)

The histone deacetylases (HDACs) are a family of eleven zinc-dependent hydrolases that regulate gene expression, chromatin architecture, microtubule dynamics, and are important targets in cancer therapy.  Individual members of this family, known as paralogs, have distinct cellular functions and subcellular localization tendencies, the exact natures of which are active areas of research.  While a number of small molecule HDAC inhibitors have been previously identified and applied to the study of HDAC function and in HDAC-based therapeutic strategies, a serious limitation of these compounds is that none are selective for individual HDAC paralogs.  Therefore, the future application of organic small molecules as probes to precisely modulate individual HDAC function or to inactivate specific family members relevant to a particular disease state depends upon the development of paralog-selective HDAC inhibitors.

With several coworkers at Harvard University, I synthesized a large collection of enantiopure 1,3-dioxanes that were structurally biased toward HDAC inhibition and had the potential to discriminate among HDAC paralogs, and then screened these molecules in a high throughput, multidimensional cytoblot assay designed to identify paralog-selective inhibitors of HDAC6.  In the course of these studies, we discovered the first paralog-selective HDAC6 inhibitor and used it to decouple the tubulin deacetylase function of HDAC6 from its histone deacetylase activity.  Researchers around the world are currently using our compound to study the role of HDAC6 in cellular processes such as microtubule polymerization and intracellular cargo transport, as well as evaluating its potential as a selective treatment for certain kinds of cancer.

II.     Synthesis of Stereochemically Diverse Molecules for Chemical Genetics

The three-dimensional contour of a molecule strongly influences how it will interact with biological macromolecules such as proteins and DNA, and thus plays an important role in determining its biologically and medicinally relevant properties.  Given the diverse array of biomolecular interaction surfaces that underlie cell and organismic function, many of which are yet to be fully characterized, it is crucial that synthetic methodology is developed to access diverse molecular shapes to complement these surfaces and thus discover new bioprobes and drugs.  My laboratory at Oberlin College explored new strategies for the synthesis of spiroketal-like molecules whose folding geometries can be modulated by adjusting the constitution and stereochemistry of their linear precursors in order to attain unprecedented molecular motifs that are likely to exhibit useful biological activity.

PUBLICATIONS

1. Hideshima, T; Bradner, J. E.; Wong, J. C.; Chauhan, D.; Richardson, P.; Schreiber, S. L.; Anderson, K. C. Small-molecule Inhibition of Proteasome and Aggresome Function Induces Synergistic Antitumor Activity in Multiple Myeloma.  Proceedings of the National Academy of Sciences, U. S. A., 2005, 102, 8567-8572.
2. Wong, J. C.; Sternson, S. M.; Louca, J. B.; Hong, R.; Schreiber, S. L. Modular Synthesis and Preliminary Biological Evaluation of Stereochemically Diverse 1,3-Dioxanes. Chemistry and Biology, 2004, 11, 1279-91.
3. Haggarty, S. J.; Clemons, P. A.; Wong, J. C.; Schreiber, S. L. Mapping Chemical Space Using Molecular Descriptors and Chemical Genetics: Deacetylase Inhibitors, Combinatorial Chemistry and High Throughput Screening, 2004, 7, 669-676.
4. Wong, J. C.; Hong, R.; Schreiber, S. L. Structural Biasing Elements For in-Cell Histone Deacetylase Paralog Selectivity. Journal of the American Chemical Society, 2003, 125, 5586-5587.
5. Haggarty, S. J.; Koeller, K. M.; Wong, J. C.; Grozinger, C. M.; Schreiber, S. L. Domain-selective Small Molecule Inhibitor of HDAC6-mediated Tubulin Deacetylation. Proceedings of the National Academy of Sciences, U. S. A., 2003, 100, 4389-4394.
6. Haggarty, S. J.; Koeller, K. M.; Wong, J. C.; Butcher, R. A.; Schreiber, S. L. Multi-dimensional Chemical Genetic Analysis of Diversity-oriented Synthesis-derived Deacetylase Inhibitors Using Cell-based Assays. Chemistry and Biology, 2003, 10, 383-396.
7. Koeller, K. M.; Haggarty, S. J.; Perkins, B. D.; Leykin, I.; Wong, J. C.; Kao, M. C.; Schreiber, S. L. Chemical Genetic Modifier Screens: Small Molecule Trichostatin Suppressors as Probes of Intracellular Histone and Tubulin Acetylation. Chemistry and Biology, 2003, 10, 397-410.
8. Sternson, S. M.; Wong, J. C.; Grozinger, C. M.; Schreiber, S. L. Synthesis of 7200 Small Molecules Based on a Substructural Analysis of the Histone Deacetylase Inhibitors Trichostatin and Trapoxin. Organic Letters, 2001, 3, 4239–4242.
9. Sternson, S. M.; Louca, J. B.; Wong, J. C.; Schreiber, S. L. Split–Pool Synthesis of 1,3-Dioxanes Leading to Arrayed Stock Solutions of Single Compounds Sufficient for Multiple Phenotypic and Protein-Binding Assays. Journal of the American Chemical Society, 2001, 123, 1740-1747.

PATENTS

Meneses, P. I.; Koehler, A. N.; Wong, J. C.; Howley, P. M.; Schreiber, S. L. Human Papillomavirus Inhibitors. U.S. Publication No. 2005-0123902, 2005.

1999-2002

Pfizer Summer Undergraduate Fellowship in Synthetic Organic Chemistry

1998

AWARDS AND HONORS 

1999-2000

1998

1997

1995

1995

VOLUNTEER EXPERIENCE 

Summer 2004

• Taught conversational English to middle school teachers in rural China in conjunction with an initiative to bring internet technology to remote regions of the country

 Summer 1999, 2002

• Worked with university students in cultural exchange and to improve their English fluency

REFERENCES

Dr. Stuart L. Schreiber

Morris Loeb Professor of Chemistry

Department of Chemistry and Chemical Biology

Harvard University

Dr. Albert R. Matlin

Professor of Chemistry

Department of Chemistry and Biochemistry

Oberlin College

Dr. Rick L. Danheiser

Professor of Chemistry

Department of Chemistry

Massachusetts Institute of Technology

Dr. Sandra Naddaff

House Master and Senior Lecturer 

Mather House

Harvard University