Gram-Scale Synthesis of the P38α MAPK-Inhibitor VX-745 for Preclinical Studies into Werner Syndrome

Bagley, Mark C.; Davis, Terence; Dix, Matthew C.; Fusillo, Vincenzo; Pigeaux, Morgane; Rokicki, Michal Jaroslaw; Kipling, David

doi:10.4155/fmc.10.217

Cited by 9 publications

(15 citation statements)

References 73 publications

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“…All three p38 inhibitors reduced the level of p-p38 in GM18366 cells to some extent but didn’t abolish it (Figure 2A). The ability of p38 inhibitors to partially prevent p38 activation has been reported previously for VX-745 and SB203580 at the concentrations used here (33). BIRB 796 is reported to completely prevent phosphorylation of p38 at 10 µM but not at 1 µM (32,37); thus, it may be expected that BIRB 796 would only partially prevent p38 activation at the concentration of 2.5 µM used here.…”

Section: Resultssupporting

confidence: 80%

“…BIRB 796 and VX-745 were synthesized according to Bagley and colleagues (32,33). For experiments using inhibitors, growth medium was supplemented with SB203580 and BIRB 796 at 2.5 µM and VX-745 at 0.5 µM.…”

Section: Methodsmentioning

confidence: 99%

“…BIRB 796 at 2.5 µM is the maximum concentration that inhibits p38 without inhibiting the related JNK1/2 kinases (34). VX-745 at 0.5 µM is the minimal concentration needed to maximally inhibit p38 (33). To maintain maximal p38 inhibition, growth medium was replaced daily with fresh EMEM-containing p38 inhibitors.…”

Section: Methodsmentioning

confidence: 99%

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Small Molecule Inhibition of p38 MAP Kinase Extends the Replicative Life Span of Human ATR-Seckel Syndrome Fibroblasts

Tivey

Rokicki

Barnacle

et al. 2013

The Journals of Gerontology: Series A

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Ataxia-telangiectasia and rad3 (ATR)-related Seckel syndrome is associated with growth retardation and premature aging features. ATR-Seckel fibroblasts have a reduced replicative capacity in vitro and an aged morphology that is associated with activation of stress-associated p38 mitogen-activated protein kinase and phosphorylated HSP27. These phenotypes are prevented using p38 inhibitors, with replicative capacity restored to the normal range. However, this stressed phenotype is retained in telomerase-immortalized ATR-Seckel fibroblasts, indicating that it is independent of telomere erosion. As with normal fibroblasts, senescence in ATR-Seckel is bypassed by p53 abrogation. Young ATR-Seckel fibroblasts show elevated levels of p21WAF1, p16INK4A, phosphorylated actin-binding protein cofilin, and phosphorylated caveolin-1, with small molecule drug inhibition of p38 reducing p16INK4A and caveolin-1 phosphorylation. In conclusion, ATR-Seckel fibroblasts undergo accelerated aging via stress-induced premature senescence and p38 activation that may underlie certain clinical features of Seckel syndrome, and our data suggest a novel target for pharmacological intervention in this human syndrome.

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Section: Resultssupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

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Small Molecule Inhibition of p38 MAP Kinase Extends the Replicative Life Span of Human ATR-Seckel Syndrome Fibroblasts

Tivey

Rokicki

Barnacle

et al. 2013

The Journals of Gerontology: Series A

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“…Moreover, it was found that pamapimod can clearly alleviate various rheumatoid arthritis symptoms when coadministered with methotrexate [136]. Besides, there are still many other inhibitors which are ongoing clinical trials as summarized in Table 4 [137–140]. …”

Section: Development Of P38-targeted Drugs As New Anti-inflammatormentioning

confidence: 99%

Functional Roles of p38 Mitogen-Activated Protein Kinase in Macrophage-Mediated Inflammatory Responses

Yang

Kim

et al. 2014

Mediators of Inflammation

311

235

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Inflammation is a natural host defensive process that is largely regulated by macrophages during the innate immune response. Mitogen-activated protein kinases (MAPKs) are proline-directed serine and threonine protein kinases that regulate many physiological and pathophysiological cell responses. p38 MAPKs are key MAPKs involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an essential role in regulating cellular processes, especially inflammation. In this paper, we summarize the characteristics of p38 signaling in macrophage-mediated inflammation. In addition, we discuss the potential of using inhibitors targeting p38 expression in macrophages to treat inflammatory diseases.

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“…The role of stress signaling in Werner syndrome cells has been investigated using a range of small molecule inhibitors ( Figure 1 ) of p38 MAPK [ 16 ], including SB203580 [ 12 , 17 , 18 ], VX-745 [ 19 , 20 , 21 ], RO3201195 [ 22 , 23 ], UR-13756 [ 24 ], and BIRB 796 [ 25 ], to study the link between replicative senescence in vitro and in vivo pathophysiology. WS fibroblasts treated with a p38 inhibitor display an unexpected reversal of the accelerated aging phenotype [ 12 ] and, as such, this may provide a suitable model for future therapeutic interventions designed to combat the aging process itself [ 12 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Microwave-Assisted Synthesis of a MK2 Inhibitor by Suzuki-Miyaura Coupling for Study in Werner Syndrome Cells

et al. 2015

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Microwave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave-assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki-Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells.

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Gram-Scale Synthesis of the P38α MAPK-Inhibitor VX-745 for Preclinical Studies into Werner Syndrome

Abstract: This method delivers the p38 inhibitor VX-745 in sufficient quantities for preclinical studies to rescue the aging phenotype in Werner syndrome.

Cited by 9 publications

References 73 publications

Small Molecule Inhibition of p38 MAP Kinase Extends the Replicative Life Span of Human ATR-Seckel Syndrome Fibroblasts

Small Molecule Inhibition of p38 MAP Kinase Extends the Replicative Life Span of Human ATR-Seckel Syndrome Fibroblasts

Functional Roles of p38 Mitogen-Activated Protein Kinase in Macrophage-Mediated Inflammatory Responses

Microwave-Assisted Synthesis of a MK2 Inhibitor by Suzuki-Miyaura Coupling for Study in Werner Syndrome Cells

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