Synthesis and evaluation of 2-{[2-(4-hydroxyphenyl)-ethyl]amino}pyrimidine-5-carboxamide derivatives as novel STAT6 inhibitors

Nagashima, S.; Yokota, Masami; Nakai, Eiichi; Kuromitsu, Sadao; Ohga, Keiko; Takeuchi, Makoto; Tsukamoto, Shin‐ichi; Ohta, Mitsuaki

doi:10.1016/j.bmc.2006.10.015

Cited by 53 publications

(35 citation statements)

References 14 publications

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“…An importance of RhoA and its downstream Rho-kinases was also demonstrated in contraction of human BSM (6), and the RhoA/Rho-kinase pathway has now been proposed as a new target for the treatment of AHR in asthma (10). In the present study, the IL-13-induced up-regulation of RhoA in hBSMCs was inhibited both by STAT6 depletion using RNA interference and by co-incubation with a STAT6 inhibitor, AS1517499 (37). Moreover, in the mice with allergic bronchial asthma, the in vivo treatment with AS1517499 inhibited both the up-regulation of RhoA and the BSM hyperresponsiveness induced by antigen exposure.…”

Section: Discussionmentioning

confidence: 76%

“…Nagashima and colleagues (37) synthesized a series of 2-f[2-(4-hydroxyphenyl)ethyl]aminogpyrimidine-5-carboxamide derivatives and evaluated their STAT6 inhibitory activities using a STAT6 reporter assay in cells stably transfected with an IL-4-responsive luciferase reporter plasmid. Among these compounds, AS1517499 showed a potent STAT6 inhibition with a 50% inhibitory concentration (IC 50 ) of 21 nM (37). AS1517499 also inhibited the IL-4-induced Th2 cell differentiation of mouse spleen T cells with an IC 50 value of 2.3 nM without influencing the IL-12-induced Th1 cell differentiation (37).…”

Section: Discussionmentioning

confidence: 98%

“…Among these compounds, AS1517499 showed a potent STAT6 inhibition with a 50% inhibitory concentration (IC 50 ) of 21 nM (37). AS1517499 also inhibited the IL-4-induced Th2 cell differentiation of mouse spleen T cells with an IC 50 value of 2.3 nM without influencing the IL-12-induced Th1 cell differentiation (37). Although the exact mechanism of inhibition of STAT6 by AS1517499 is unclear, the parent compound TMC-264 is known to inhibit both tyrosine phosphorylation of STAT6, with an IC 50 value of 1 .6 mM (1,600 nM), and the complex formation of phosphorylated STAT6 with its recognition DNA sequence (46).…”

Section: Discussionmentioning

confidence: 99%

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A Novel STAT6 Inhibitor AS1517499 Ameliorates Antigen-Induced Bronchial Hypercontractility in Mice

Chiba

Todoroki²,

Nishida³

et al. 2009

Am J Respir Cell Mol Biol

120

104

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Interleukin-13 (IL-13) is one of the central mediators for development of airway hyperresponsiveness in asthma. The signal transducer and activation of transcription 6 (STAT6) is one of the major signal transducers activated by IL-13, and a possible involvement of IL-13/STAT6 pathway in the augmented bronchial smooth muscle (BSM) contraction has been suggested. In the present study, the effect of a novel STAT6 inhibitor, AS1517499, on the development of antigen-induced BSM hyperresponsiveness was investigated. In cultured human BSM cells, IL-13 (100 ng/ml) caused a phosphorylation of STAT6 and an up-regulation of RhoA, a monomeric GTPase responsible for Ca2+ sensitization of smooth muscle contraction: both events were inhibited by co-incubation with AS1517499 (100 nM). In BALB/c mice that were actively sensitized and repeatedly challenged with ovalbumin antigen, an increased IL-13 level in bronchoalveolar lavage fluids and a phosphorylation of STAT6 in bronchial tissues were observed after the last antigen challenge. These mice had an augmented BSM contractility to acetylcholine together with an up-regulation of RhoA in bronchial tissues. Intraperitoneal injections of AS1517499 (10 mg/kg) 1 hour before each ovalbumin exposure inhibited both the antigen-induced up-regulation of RhoA and BSM hyperresponsiveness, almost completely. A partial but significant inhibition of antigen-induced production of IL-13 was also found. These findings suggest that the inhibitory effects of STAT6 inhibitory agents, such as AS1517499, both on RhoA and IL-13 up-regulations might be useful for asthma treatment.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Novel STAT6 Inhibitor AS1517499 Ameliorates Antigen-Induced Bronchial Hypercontractility in Mice

Chiba

Todoroki²,

Nishida³

et al. 2009

Am J Respir Cell Mol Biol

120

104

View full text Add to dashboard Cite

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“…Incubation time and concentration of IL-13 inhibitors used were determined in B-cell lines such as Raji and SKW 6.4 (data not shown). IL-4 was inhibited with an anti-IL-4 antibody (10 mg/mL, R&D Systems), whereas pSTAT-6 inhibition was obtained with the specific pSTAT-6 inhibitor AS1517499 44 (100 nM, 45 Axon, Medchem). All cultures were performed in complete RPMI 1640 medium (GIBCO, Invitrogen) in the presence of rhIL-2 (10 ng/mL, PeproTech) and IL-7 (5 ng/mL, PeproTech).…”

Section: Cd4mentioning

confidence: 99%

Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation

Geskin¹,

Viragova²,

Stolz

et al. 2015

Blood

131

113

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Key Points• IL-13 is an autocrine factor for CTCL.• IL-13 and its receptors represent novel markers of CTCL malignancy and potential therapeutic targets for intervention.Cutaneous T-cell lymphomas (CTCLs) primarily affect skin and are characterized by proliferation of mature CD4 1 T-helper cells. The pattern of cytokine production in the skin and blood is considered to be of major importance for the pathogenesis of CTCLs. Abnormal cytokine expression in CTCLs may be responsible for enhanced proliferation of the malignant cells and/or depression of the antitumor immune response. Here we show that interleukin-13 (IL-13) and its receptors IL-13Ra1 and IL-13Ra2 are highly expressed in the clinically involved skin of CTCL patients. We also show that malignant lymphoma cells, identified by the coexpression of CD4 and TOX (thymus high-mobility group box), in the skin and blood of CTCL patients produce IL-13 and express both receptors. IL-13 induces CTCL cell growth in vitro and signaling through the IL-13Ra1. Furthermore, antibody-mediated neutralization of IL-13 or soluble IL-13Ra2 molecules can lead to inhibition of tumor-cell proliferation, implicating IL-13 as an autocrine factor in CTCL. Importantly, we established that IL-13 synergizes with IL-4 in inhibiting CTCL cell growth and that blocking the IL-4/IL-13 signaling pathway completely reverses tumor-cell proliferation. We conclude that IL-13 and its signaling mediators are novel markers of CTCL malignancy and potential therapeutic targets for intervention. (Blood. 2015;125(18):2798-2805

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“…Nonetheless, according to reports, AS1517499 (UNII--2H31HOT08T), soluble in purified DMSO, is a potent and selective STAT6 inhibitor with an IC50 of 21 nM. 46 This compound is a novel p-STAT6 inhibitor that was synthesized based on the structure of a previously reported STAT6 inhibitor, TMC-264, discovered from the fungus Phoma.…”

Section: Discussionmentioning

confidence: 99%

STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia

Zha¹

2017

EJEA

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Synthesis and evaluation of 2-{[2-(4-hydroxyphenyl)-ethyl]amino}pyrimidine-5-carboxamide derivatives as novel STAT6 inhibitors

Cited by 53 publications

References 14 publications

A Novel STAT6 Inhibitor AS1517499 Ameliorates Antigen-Induced Bronchial Hypercontractility in Mice

A Novel STAT6 Inhibitor AS1517499 Ameliorates Antigen-Induced Bronchial Hypercontractility in Mice

Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation

STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia

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