Despite huge advances in our understanding of the molecular mechanisms that drive the neoplastic process, the mainstays of cancer therapy have changes relatively little. New sources of small molecules are required to counter the alterations in protein function that occur as a result of the mutations that give rise to cancer. We therefore need general strategies that can identify small molecules that activate or inhibit the function of specific proteins. Accomplishing this goal is the central mission of the newly-formed Harvard Institute of Chemistry and Cell Biology (ICCB): to develop general methods for creating cell-permeable small molecules that can be used to manipulate the function of any given protein target. By developing a system that makes this process routine, we aim to exploit the tools of chemistry to generate a powerful interface between genomics, biology and medicine. In this Program Project, we will develop new chemistry and screening technologies, and apply these to biological assays relevant to cancer. In Project 1, we will use the full ranges of modern synthetic methods combined the split-pool synthesis strategy to produce large combinatorial libraries of small molecules that have natural-product-like structures. In Project 2, we will develop a high-throughput, nanoliter-volume screening format that will enable us to screen these libraries. We will also develop a general method for small-molecule-dependent genetic selections in yeast, and a general approach to identification of the protein targets of small molecules. In Project 3, we will create a range of """"""""smart assays"""""""" relevant to cancer that seek to identify inhibitors of proteins involved in cell cycle control, cytoskeleton function and DNA repair. The elements of this Program Project are highly interrelated. The assays developed in Project 3 will make use of the new screening formats developed in Project 2, and will be used to screen the libraries made in Project 1. The Synthetic Chemistry Core will supply monomers to Project 1 for library synthesis, and will resynthesize compounds discovered in the screens performed in Projects 2 and 3 for further study. The Synthetic Chemistry Core will also synthesize small libraries focused on the identified leads for analysis of structure-activity relationships. The Administrative Core will coordinate both the scientific efforts and the budget management of the research teams.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA078048-02S1
Application #
6131275
Study Section
Special Emphasis Panel (ZCA1 (J2))
Program Officer
Arya, Suresh
Project Start
1998-05-15
Project End
2003-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Shi, Jue; Mitchison, Timothy J (2017) Cell death response to anti-mitotic drug treatment in cell culture, mouse tumor model and the clinic. Endocr Relat Cancer 24:T83-T96
Bradner, James E; West, Nathan; Grachan, Melissa L et al. (2010) Chemical phylogenetics of histone deacetylases. Nat Chem Biol 6:238-243
Gatlin, Jesse C; Matov, Alexandre; Danuser, Gaudenz et al. (2010) Directly probing the mechanical properties of the spindle and its matrix. J Cell Biol 188:481-9
Tolopko, Andrew N; Sullivan, John P; Erickson, Sean D et al. (2010) Screensaver: an open source lab information management system (LIMS) for high throughput screening facilities. BMC Bioinformatics 11:260
Kawada, Junichi; Zou, Ping; Mazitschek, Ralph et al. (2009) Tubacin kills Epstein-Barr virus (EBV)-Burkitt lymphoma cells by inducing reactive oxygen species and EBV lymphoblastoid cells by inducing apoptosis. J Biol Chem 284:17102-9
Gatlin, Jesse C; Matov, Alexandre; Groen, Aaron C et al. (2009) Spindle fusion requires dynein-mediated sliding of oppositely oriented microtubules. Curr Biol 19:287-96
Huang, Hsiao-Chun; Shi, Jue; Orth, James D et al. (2009) Evidence that mitotic exit is a better cancer therapeutic target than spindle assembly. Cancer Cell 16:347-58
Birmingham, Amanda; Selfors, Laura M; Forster, Thorsten et al. (2009) Statistical methods for analysis of high-throughput RNA interference screens. Nat Methods 6:569-75
Wang, Qiu; Schreiber, Stuart L (2009) Copper-mediated amidation of heterocyclic and aromatic C-H bonds. Org Lett 11:5178-80
Tsui, Melody; Xie, Tiao; Orth, James D et al. (2009) An intermittent live cell imaging screen for siRNA enhancers and suppressors of a kinesin-5 inhibitor. PLoS One 4:e7339

Showing the most recent 10 out of 54 publications