Pyrazole Urea-Based Inhibitors of p38 MAP Kinase:  From Lead Compound to Clinical Candidate

Regan, John; Breitfelder, Steffen; Cirillo, Pier F.; Gilmore, Thomas D.; Graham, Anne G.; Hickey, Eugene R.; Bernhard, Klaus; Madwed, Jeffrey; Moriak, Monica; Moss, Neil; Pargellis, Christopher A.; Pav, Sue; Proto, Alfred; Swinamer, Alan; Tong, Liang; Torcellini, Carol A.

doi:10.1021/jm020057r

Cited by 353 publications

(264 citation statements)

References 48 publications

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“…The TAK1 inhibitor NG-25 (28), the IKKβ inhibitor BI605906 (20), KF-1B (29,30), MRT67307 (31), BIRB0796 (32), and PD0325901 (33) were synthesized as described. The TLR7 agonists, CL097 (catalog no.…”

Section: Methodsmentioning

confidence: 99%

Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells

López-Peláez

Lamont

Peggie

et al. 2014

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

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The siRNA knockdown of IFN Regulatory Factor 5 (IRF5) in the human plasmacytoid dendritic cell line Gen2.2 prevented IFNβ production induced by compound CL097, a ligand for Toll-like receptor 7 (TLR7). CL097 also stimulated the phosphorylation of IRF5 at Ser462 and stimulated the nuclear translocation of wild-type IRF5, but not the IRF5[Ser462Ala] mutant. The CL097-stimulated phosphorylation of IRF5 at Ser462 and its nuclear translocation was prevented by the pharmacological inhibition of protein kinase IKKβ or the siRNA knockdown of IKKβ or its "upstream" activator, the protein kinase TAK1. Similar results were obtained in a murine macrophage cell line stimulated with the TLR7 agonist compound R848 or the nucleotide oligomerization domain 1 (NOD1) agonist KF-1B. IKKβ phosphorylated IRF5 at Ser462 in vitro and induced the dimerization of wild-type IRF5 but not the IRF5[S462A] mutant. These findings demonstrate that IKKβ activates two "master" transcription factors of the innate immune system, IRF5 and NF-κB.T he transcription factor IFN Regulatory Factor 5 (IRF5) has a critical role in the production of proinflammatory cytokines. The secretion of interleukin 12 (IL-12), IL-6, and TNFα by ligands that activate Toll-like receptor 3 (TLR3), TLR4, TLR5, and TLR9, is greatly impaired in macrophages, conventional dendritic cells (cDCs), and plasmacytoid dendritic cells (pDCs) of mice that do not express IRF5 (1). However, the role of IRF5 in type 1 IFN production in pDCs has been less clear. The TLR9-stimulated secretion of IFNα was initially reported to be similar in pDCs from IRF5-deficient and wild-type mice (1), but a later study found that the TLR7-or TLR9-stimulated production of IFNα was reduced in pDCs from IRF5-deficient mice (2). Subsequently, some IRF5-deficient mouse lines were shown to carry a second mutation in the gene encoding the guanine nucleotide exchange factor (dedicator of cytokinesis 2 (Dock2), and it was reported that TLR9-stimulated IFNα secretion was largely intact in pDCs from mice where this secondary mutation had been eliminated (3). A further study using pDCs from IRF5-deficient mice, carrying or not carrying the DOCK2 mutation, confirmed that IRF5 had little effect on TLR9-stimulated IFNα secretion, but indicated an important role for IRF5 in the secretion of IFNβ (4). IRF5 was also required for the TLR9-stimulated production of IFNβ in the human pDC line CAL-1 (5) and for the production of IFNβ induced by streptococcal RNA in cDCs (6) and by the fungal pathogen Candida albicans in a pathway dependent on the Dectin 1 and Dectin 2 receptors (7). IRF5 was also found to be needed for the production of IFNβ by a small subset of viruses (8, 9). Thus, IRF5 does appear to be a key regulator of IFNβ production by several pathogens.IRF5 is present in a latent form in the cell cytosol but accumulates in the nucleus to stimulate gene transcription following viral infection (10, 11) or stimulation with the TLR7/TLR8 agonist R848 (9). The nuclear export signal (NES) (12) of IRF5 therefore appears to ...

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Section: Methodsmentioning

confidence: 99%

Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells

López-Peláez

Lamont

Peggie

et al. 2014

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

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“…For VX680 treatment, drugs (25 mg/kg) were administered intraperitoneally (i.p.) twice a day for 14 d. 11 BIRB796 (10 mg/kg) was administrated orally the next day of VX680 treatment for the first time, and then it was applied every 3 d. 61 The tumor sizes were estimated with a caliper. A standard formula (width2 £length £ 0.52) was used for calculating the volumes of tumors.…”

Section: Antitumor Study Of Human Tumor Xenografts In Nude Micementioning

confidence: 99%

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

Jin

Zhang

et al. 2016

Cancer Biology & Therapy

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VX680 is a potent and selective inhibitor that targets the Aurora kinase family. The p38 mitogen-activated protein kinase (MAPK) regulates a large number of cellular pathways and plays an important role in the regulation of cell survival and apoptosis. This study aimed to evaluate the effect of VX680 on cervical cancer cells and investigate whether the effects on apoptosis are enhanced by the ablation of p38 MAPK activation. The results suggested that VX680 inhibited the proliferation of cervical cancer cells by causing G2/M phase arrest and endoreduplication and that the apoptotic effect was attenuated by the activation of p38 MAPK. However, the addition of BIRB796, which is an important p38 MAPK inhibitor, effectively eliminated the expression of p-p38 and hence significantly enhanced the cell death induced by VX680 in vitro. Further study demonstrated that BIRB796 cooperated with VX680 to suppress cervical cancer cell growth in a mouse xenograft model. Taken together, our results demonstrated that VX680 induced cell cycle arrest and endoreduplication in human cervical cancer cells. Combined treatment with VX680 and BIRB796 synergistically inhibited tumor growth both in vitro and in vivo. Dual blockade of Aurora kinases and p38 MAPK is therefore a promising strategy for cervical cancer treatment.

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“…22,23 This encouraged us to synthesize a number of different unknown pyrazolylurea derivatives. The key intermediate for this objective is the 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid azide (11), which was prepared in a two-step sequence starting from the pyrazolecarboxaldehyde 1.…”

Section: Methodsmentioning

confidence: 99%

New pyrazole derivatives of potential biological activity

Farghaly¹,

Esmail²,

Abdel‐Hafez³

et al. 2012

Arkivoc

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5-Chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxaldehyde (1) was reacted with hydrazine hydrate and thiosemicarbazide to afford the corresponding hydrazones 2 and thiosemicarbazones 4. The latter compounds were used to obtain the pyrazole derivatives 3, 5-7. A series of azines 8a-e were obtained by reacting 2 with aromatic aldehydes. Potassium permanganate oxidation of 1 gave the acid 9, which was transformed into the corresponding acid azide 11 then used to prepare diverse urea derivatives 13-18 via Curtius reaction.

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Pyrazole Urea-Based Inhibitors of p38 MAP Kinase: From Lead Compound to Clinical Candidate

Cited by 353 publications

References 48 publications

Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells

Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

New pyrazole derivatives of potential biological activity

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