Single-step synthesis of cell-permeable protein dimerizers that activate signal transduction and gene expression

Journal of the American Chemical Society

Volumn 119, Issue 22, 1997, Pages 5106-5109

  Diver, Steven T ^a   Schreiber, Stuart L ^a  

^a HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALKENE; CHEMICAL COMPOUND; PROTEIN; TACROLIMUS;

ARTICLE; DIMERIZATION; GENE ACTIVATION; SIGNAL TRANSDUCTION; SYNTHESIS;

EID: 0030759476     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja963891c     Document Type: Article

References (30)

1. (a) Spencer, D. M.; Wandless, T. J.; Schreiber, S. L.; Crabtree, G. R. Science 1993, 262, 1019.
2. (b) Pruschy, M. N.; Spencer, D. M.; Kapoor, T. M.; Miyake, H.; Crabtree, G. R.; Schreiber, S. L. Chem. Biol. 1994, 1, 164.
3. (a) Belshaw, P. J.; Spencer, D. M.; Crabtree, G. R.; Schreiber, S. L. Chem. Biol. 1996, 3, 731.
4. (b) Spencer, D. M.; Belshaw, P. J.; Chen, L.; Ho, S. N.; Randazzo, F.; Crabtree, G. R.; Schreiber, S. L. Curr. Biol. 1996, 6, 839.
5. Spencer, D. M.; Graef, I.; Austin, D. J.; Schreiber, S. L.; Crabtree, G. R. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 9805.
6. Holsinger, L. J.; Spencer, D. M.; Austin, D. J.; Schreiber, S. L. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 9810.
7. (a) Luo, Z.; Tzivion, G.; Belshaw, P. J.; Vavvas, D.; Marshall, M.; Avruch, J. Nature 1996, 383, 181.
8. (b) Farrar, M. A.; Alberola-Ila, J.; Perlmutter, R. M. Nature 1996, 383, 178.
9. Ho, S. N.; Biggar, S. R.; Spencer, D. M.; Schreiber, S. L.; Crabtree, G. R. Nature 1996, 382, 822.
10. Yang, J.; Mercola, M.; Schreiber, S. L. Unpublished results.
11. Rivera, V. M.; Clackson, T.; Natesan, S.; Pollock, R.; Amara, J. F.; Keenan, T.; Magari, S. R.; Phillips, T.; Cerasoli, F., Jr.; Holt, D. A.; Gilman, M. Nature (Medicine) 1996, 2, 1028.
12. (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100.
13. (b) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856.
14. (c) Miller, S.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 5855.
15. (d) Clark, T. D.; Ghadiri, M. R. J. Am. Chem. Soc. 1995, 117, 12363.
16. The stereoselectivity of the metathesis proved relatively insensitive to solvent effects and temperature. However, modest E-selectivity (4:1 E/Z) could be achieved by conducting the "dimerization" in refluxing t-BuOH (23% isolated yield). Heating in DCM or DCE did not affect the selectivity Improved Z-selectivity (3:1 Z/E) could be obtained by TBS protection of the C-24 hydroxyl group. Efforts to interconvert the geometric isomers resulted only in decomposition.
17. (a) Vroman, H. E.; Cohen, C. F. J. Lipid Res. 1967, 8, 150.
18. (b) de Vries, B. Chem. Ind. (Britain) 1962, 1049. The isomers 3E and 3Z were not separable on untreated silica gel under identical conditions. Analysis of isomeric purity was possible by RP hplc (see Experimental Section).
19. Breitmaier, E.; Voelter, W. Carbon-13 NMR Spectroscopy. High Resolution Methods and Applications in Organic Chemistry and Biochemistry, VCH: New York, 1987; pp 192-195.
20. (a) Bierer, B. E.; Matilla, P. S.; Standaert, R. F.; Herzenberg, L. A.; Burakoff, S. J.; Crabtree, G.; Schreiber, S. L. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 9231.
21. (b) Harding, M. W.; Galat, A.; Uehling, D. E.; Schreiber, S. L. Nature 1989, 341, 758.
22. See Supplemental Material.
23. Austin, D. J.; Crabtree, G. R.; Schreiber, S. L. Chem. Biol. 1994, 1, 131.
24. Liu, J.; Farmer, J. D.; Lane, W. S.; Friedman, J.; Weissman, I.; Schreiber, S. L. Cell 1991, 66, 807-815.
25. Diver, S. T.; Schreiber, S. L. Unpublished results.
26. Yang, J.; Schreiber, S. L. Unpublished results.
27. Preliminary data indicate that FK1012H2 4 is twice as potent and has about ten times the metabolic stability of FK1012A 5 in transgenic mice expressing a CID-responsive fusion protein. Spencer, D. Unpublished results.
28. Fischer, G.; Wittman-Liebold, B.; Lang, K.; Kiefhaber, T.; Schmid, F. X. Nature 1989, 337, 476. Swain, C. G.; Swain, M. S.; Berg, L. F. J. Chem. Inf. Comput. Sci. 1980, 20, 47.
29. Fischer, G.; Wittman-Liebold, B.; Lang, K.; Kiefhaber, T.; Schmid, F. X. Nature 1989, 337, 476. Swain, C. G.; Swain, M. S.; Berg, L. F. J. Chem. Inf. Comput. Sci. 1980, 20, 47.
30. Standaert, R. F.; Galat, A.; Verdine, G. L.; Schreiber, S. L. Nature 1990, 346, 671.