Target: Interaction Domains

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Science's STKE  25 May 2004:
Vol. 2004, Issue 234, pp. tw185
DOI: 10.1126/scisignal.2342004tw185

Two groups report the design of small molecule inhibitors of protein-protein interactions. Roehrl et al. used a fluorescence polarization assay to screen for molecules that would inhibit the recognition of nuclear factor of activated T cells (NFAT) by the phosphate calcineurin. Molecules were identified that decreased the fluorescence of a fluorescently tagged short peptide (VIVIT) that was known to interfere with the NFAT-calcineurin interaction. Molecules that completely displaced VIVIT were analyzed further. In addition to confirming the interaction of these molecules with calcineurin, the authors showed that one of them, INCA-6, blocked NFAT dephosphorylation, NFAT nuclear translocation, and stimulation of NFAT-dependent gene expression in cultured T cells. Calcineurin in lysates from cells exposed to INCA-6 retained catalytic activity. Gao et al. used a structure-based virtual screen to identify small molecules that would fit in the site on the Rac guanosine triphosphatase (GTPase) where its guanine exchange factor (GEF) interacts. Each GTPase has a selective GEF that stimulates it. Gao et al. identified a small molecule, NSC23766, that selectively blocked the interaction between Rac1 and its GEFs, TrioN and Tiam1, but did not affect the interaction between other GTPases and their GEFs. NSC23766 not only blocked GEF binding but also inhibited nucleotide exchange on Rac1. In cultured fibroblasts (NIH 3T3 cells), NSC23766 inhibited Rac activation, the formation of lamellipodia, and cell proliferation in response to growth factors. NSC23766 inhibited colony growth in soft agar caused by overexpression of Tiam1 and inhibited proliferation, anchorage-independent growth, and invasiveness of PC-3 prostate tumor cells. These two papers demonstrate the effectiveness of targeting protein interaction domains.

M. H. A. Roehrl, S. Kang, J. Aramburu, G. Wagner, A. Rao, P. G. Hogan, Selective inhibition of calcineurin-NFAT signaling by blocking protein-protein interaction with small organic molecules. Proc. Natl. Acad. Sci. U.S.A. 101, 7554-7559 (2004). [Abstract] [Full Text]

Y. Gao, J. B. Dickerson, F. Guo, J. Zheng, Y. Zheng, Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc. Natl. Acad. Sci. U.S.A. 101, 7618-7623 (2004). [Abstract] [Full Text]

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