This renewal grant application seeks funding for a project that uses organic compounds that bind two proteins simultaneously in order to activate cellular processes including protein translocation, signal transduction, and gene transcription. Activation results from the increased effective molarity of a target protein in the vicinity of another protein, usually one having an enzymatic activity (for example, a kinase, polymerase, protease). Transferal of information by altering the effective molarity of proteins, often through adapter proteins, is becoming recognized as a fundamental principle in biology, rivaling the allosteric mechanism. The """"""""dimerizer"""""""" project was initiated four years ago, when their principle was not generally recognized and certainly not widely accepted. Our premise was that if effective molarity was the key to controlling cellular processes, we could control these processes by synthesizing cell permeable, """"""""small molecules"""""""" that increase the effective molarity of, for example, protein substrates of enzymes. The now widespread acceptance of the role of effective molarity in biology is due in part of the success of the dimerizer project. The project has also provided the first general approach to controlling protein function by activation in cells, tissues, and animals. Understanding a protein's function often requires altering its function. This has been most frequently accomplished by genetic manipulation, i.e. mutation the gene encoding a protein of interest. Alternatively, it is possible to alter protein function directly, using small molecules that bind to the target protein (chemical genetic approach). Inactivation (equivalent to a """"""""loss of function"""""""") to become a common outcome. The planned research is expected to play a vital role in extending the chemical genetic approach by using small molecule dimerizers to understand and control the cellular, development, and physiological function of several target proteins and pathways. The planned research is aimed at making optimal reagents available to the scientific community and at illustrating their use in the context of several vexing problems in biology, including the mechanism of signaling through the insulin receptor and the ability to control that signaling with small molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM052067-06
Application #
6125332
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Schwab, John M
Project Start
1994-12-01
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
6
Fiscal Year
2000
Total Cost
$305,753
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Micalizio, Glenn C; Schreiber, Stuart L (2002) A boronic ester annulation strategy for diversity-oriented organic synthesis. Angew Chem Int Ed Engl 41:152-4
Nghiem, Paul; Park, Peter K; Kim Ys, Yong-son et al. (2002) ATR is not required for p53 activation but synergizes with p53 in the replication checkpoint. J Biol Chem 277:4428-34
Clemons, Paul A; Gladstone, Brian G; Seth, Abhinav et al. (2002) Synthesis of calcineurin-resistant derivatives of FK506 and selection of compensatory receptors. Chem Biol 9:49-61
Tallarico, J A; Depew, K M; Pelish, H E et al. (2001) An alkylsilyl-tethered, high-capacity solid support amenable to diversity-oriented synthesis for one-bead, one-stock solution chemical genetics. J Comb Chem 3:312-8
Blackwell, H E; Clemons, P A; Schreiber, S L (2001) Exploiting site-site interactions on solid support to generate dimeric molecules. Org Lett 3:1185-8
Blackwell, H E; Perez, L; Stavenger, R A et al. (2001) A one-bead, one-stock solution approach to chemical genetics: part 1. Chem Biol 8:1167-82
Clemons, P A; Koehler, A N; Wagner, B K et al. (2001) A one-bead, one-stock solution approach to chemical genetics: part 2. Chem Biol 8:1183-95
Nghiem, P; Park, P K; Kim , Y et al. (2001) ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation. Proc Natl Acad Sci U S A 98:9092-7
Clemons, P A (1999) Design and discovery of protein dimerizers. Curr Opin Chem Biol 3:112-5
Schmidt, D R; Schreiber, S L (1999) Molecular association between ATR and two components of the nucleosome remodeling and deacetylating complex, HDAC2 and CHD4. Biochemistry 38:14711-7

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