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PNAS 101 (20): 7554-7559

Copyright © 2004 by the National Academy of Sciences.


Biochemistry

Selective inhibition of calcineurin-NFAT signaling by blocking protein–protein interaction with small organic molecules

Michael H. A. Roehrl *, {dagger} {ddagger}, Sunghyun Kang {ddagger}, §, ¶, José Aramburu ||, Gerhard Wagner *, **, Anjana Rao §, ¶, and Patrick G. Hogan ¶, **

Departments of *Biological Chemistry and Molecular Pharmacology and §Pathology, Harvard Medical School, Boston, MA 02115; {dagger}Ph.D. Program in Biological and Biomedical Sciences, Division of Medical Sciences, Faculty of Arts and Sciences, Harvard University, Boston, MA 02115; Center for Blood Research, 200 Longwood Avenue, Boston, MA 02115; and ||Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain

Communicated by Stephen C. Harrison, Harvard Medical School, Boston, MA, April 5, 2004

Received for publication October 31, 2003.

Abstract: Transient or reversible protein–protein interactions are commonly used to ensure efficient targeting of signaling enzymes to their cellular substrates. These interactions include direct binding to substrate, interaction with an accessory or scaffold protein, and positioning at subcellular locations in proximity to substrates. The existence of specialized targeting mechanisms raises the possibility of designing inhibitors that do not block enzyme activity per se, but rather interfere with targeting of the enzyme to one or more of its substrates within the cell. Here, we identify small organic molecules that specifically block targeting of the protein phosphatase calcineurin to its substrate nuclear factor of activated T cells (NFAT, also termed NFATc) and show that they are effective inhibitors of calcineurin-NFAT signaling.


Abbreviations: NFAT, nuclear factor of activated T cells; CsA, cyclosporin A; INCA, inhibitor of NFAT-calcineurin association; PMA, phorbol 12-myristate 13-acetate; TNF, tumor necrosis factor.

{ddagger} M.H.A.R. and S.K. contributed equally to this work.

** To whom correspondence may be addressed. E-mail: hogan{at}cbr.med.harvard.edu or gerhard_wagner{at}hms.harvard.edu.

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