3,5-Bis(trifluoromethyl)pyrazoles:  A Novel Class of NFAT Transcription Factor Regulator

Djurić, Stevan W.; Bamaung, Nwe Y.; Basha, Anwer; Liu, Huaqing; Luly, Jay R.; Madar, David J.; Sciotti, Richard J.; Tu, Noah P.; Wagenaar, Frank L.; Wiedeman, Paul E.; Zhou, Xun; Ballaron, Stephen J.; Bauch, Joy; Chen, Y.-W.; Chiou, X. Grace; Fey, Thomas A.; Gauvin, Donna M.; Gubbins, Earl J.; Hsieh, Gin C.; Marsh, Kennan C.; Mollison, Karl W.; Pong, Melissa; Shaughnessy, Thomas K.; Sheets, Michael P.; Smith, Morey L.; Trevillyan, James M.; Warrior, Usha; Wegner, Craig D.; Carter, G. W.

doi:10.1021/jm990615a

Cited by 109 publications

(67 citation statements)

References 21 publications

(22 reference statements)

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“…We have previously reported the chemical synthesis and optimization of the bistrifluoromethyl pyrazole series of cytokine inhibitors with respect to bioavailability, half-life, and efficacy to inhibit IL-2 synthesis in rodents and nonhuman primates (32). This report extends these findings by providing evidence that the BTP compounds work at the level of NFAT regulation.…”

Section: Discussionsupporting

confidence: 52%

“…As shown in Fig. 9, A, phosphorylated Elk-1c (pElk-1) is dephosphorylated (as measured by a decrease in 32 P content and an increase in electrophoretic mobility) when incubated with COS-7 cell lysate. The dephosphorylation of pElk-1 is inhibited in a dosedependent fashion by the addition of CsA or EGTA to the cell lysates (Fig.…”

Section: Btp Compounds Fail To Inhibit Can Activity In Cellmentioning

confidence: 81%

“…In vitro phosphatase assays were performed using phosphorylated GST-Elk-1c as a substrate. 32 P-Labeled GST-Elk-1c was prepared by incubating with active MEK1 and ERK1 in kinase buffer (18 mM HEPES, pH 7.5, 10 mM magnesium acetate, and 50 M ATP) for 30 min at 30°C in the presence of [␥-…”

Section: Il-2 Reporter Gene Expression In Jurkat E2mentioning

confidence: 99%

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Potent Inhibition of NFAT Activation and T Cell Cytokine Production by Novel Low Molecular Weight Pyrazole Compounds

Trevillyan

Chiou

Chen

et al. 2001

Journal of Biological Chemistry

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Engagement of the T cell antigen receptor (TcR)1 with the antigen-major histocompatibility complex on antigen-presenting cells triggers a complex TcR signaling cascade that leads to T cell activation and cytokine secretion (1). During this process, T cells express the autocrine growth factor interleukin 2 (IL-2), which promotes T cell proliferation by interacting with the IL-2 receptor, which is also up-regulated on activated T cells. The transcriptional regulation of the IL-2 gene has been extensively analyzed at the IL-2 promoter, a 275-bp region located upstream of the transcriptional start site of the gene (2, 3). Several transcription factors have been identified to bind elements within this regulatory region, including AP-1, NF-B, and the nuclear factor of activated T cells (NFAT) (2).The transcription factor NFAT plays an essential role in IL-2 expression. Binding sites for NFATs have also been found within the promoter regions of several other cytokine genes, including IL-3, IL-4, IL-5, IL-8, IL-13, tumor necrosis factor ␣, granulocyte-macrophage colony-stimulating factor, and ␥-IFN (4, 5). NFAT is a complex composed of a cytoplasmic subunit and an inducible nuclear component comprised of AP-1 (Fos/ Jun) family members. At least four structurally related NFAT cytoplasmic subunit members, NFATp/NFAT1, NFATc/ NFAT2, NFAT3, and NFATX/NFATc3/NFAT4, have been identified (5). NFAT proteins share a conserved domain located toward the C terminus (6) that binds DNA and also participates in cooperative protein-protein interactions with AP-1 transcription factors (7,8). Immediately N-terminal to the DNA-binding domain is a second conserved module of ϳ300 residues known as the NFAT homology (NFAT-h) region. The N terminus of NFAT, including the NFAT-h region, regulates nuclear/cytoplasm trafficking in response to changes in intracellular Ca 2ϩ concentrations. In resting T cells, the protein is retained in the cytoplasm and its NFAT-h domain is heavily phosphorylated. Engagement of the TcR or treatment of cells with the Ca 2ϩ ionophore activates the Ca 2ϩ /calmodulin-dependent Ser/Thr phosphatase, calcineurin. CaN dephosphorylates the NFAT-h domain, resulting in translocation of NFAT to the nucleus (9).

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Section: Discussionsupporting

confidence: 52%

Section: Btp Compounds Fail To Inhibit Can Activity In Cellmentioning

confidence: 81%

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Potent Inhibition of NFAT Activation and T Cell Cytokine Production by Novel Low Molecular Weight Pyrazole Compounds

Trevillyan

Chiou

Chen

et al. 2001

Journal of Biological Chemistry

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“…BTPs were originally identified as inhibitors of T lymphocyte activation (24). Several reports have suggested that BTP2 (Pyr2) is a potent inhibitor for both Ca 2ϩ release-activated Ca 2ϩ (CRAC) channels and TRPC channels and for NFAT-driven IL-2 production (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…Bis(trifluoromethyl)pyrazoles (BTPs) are a class of pyrazole derivatives that act as potent immunosuppressive compounds by inhibiting cytokine release from human lymphocytes and suppressing T cell proliferation (24). The BTP derivative 4-methyl-4Ј-[3,5-bis(trif luoromethyl)-1H-pyrazol-1-yl]-1,2,3-thiadiazole-5-carboxanilide, BTP2 (YM-58483), was shown to block SOCs in T lymphocytes and TRPC channels in HEK293 cells (25)(26)(27).…”

Section: Canonical Transient Receptor Potential (Trpc) Channels Contrmentioning

confidence: 99%

Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound

Kiyonaka

Kato

Nishida

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

336

318

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Canonical transient receptor potential (TRPC) channels control influxes of Ca 2؉ and other cations that induce diverse cellular processes upon stimulation of plasma membrane receptors coupled to phospholipase C (PLC). Invention of subtype-specific inhibitors for TRPCs is crucial for distinction of respective TRPC channels that play particular physiological roles in native systems. Here, we identify a pyrazole compound (Pyr3), which selectively inhibits TRPC3 channels. Structure-function relationship studies of pyrazole compounds showed that the trichloroacrylic amide group is important for the TRPC3 selectivity of Pyr3. Electrophysiological and photoaffinity labeling experiments reveal a direct action of Pyr3 on the TRPC3 protein. In DT40 B lymphocytes, Pyr3 potently eliminated the Ca 2؉ influx-dependent PLC translocation to the plasma membrane and late oscillatory phase of B cell receptorinduced Ca 2؉ response. Moreover, Pyr3 attenuated activation of nuclear factor of activated T cells, a Ca 2؉ -dependent transcription factor, and hypertrophic growth in rat neonatal cardiomyocytes, and in vivo pressure overload-induced cardiac hypertrophy in mice. These findings on important roles of native TRPC3 channels are strikingly consistent with previous genetic studies. Thus, the TRPC3-selective inhibitor Pyr3 is a powerful tool to study in vivo function of TRPC3, suggesting a pharmaceutical potential of Pyr3 in treatments of TRPC3-related diseases such as cardiac hypertrophy.Ca 2ϩ signaling ͉ pyrazole compounds ͉ TRPC channels ͉ TRPC3

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Chlorodifluoromethane

Burton¹,

Qiu²,

Jończyk³

et al. 2010

Encyclopedia of Reagents for Organic Synthesis

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3,5-Bis(trifluoromethyl)pyrazoles: A Novel Class of NFAT Transcription Factor Regulator

Cited by 109 publications

References 21 publications

Potent Inhibition of NFAT Activation and T Cell Cytokine Production by Novel Low Molecular Weight Pyrazole Compounds

Potent Inhibition of NFAT Activation and T Cell Cytokine Production by Novel Low Molecular Weight Pyrazole Compounds

Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound

Chlorodifluoromethane

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