KR-003048, a potent, orally active inhibitor of p38 mitogen-activated protein kinase

Montalbán, Antonio; Boman, Erik; Chang, Chau-Dung; Ceide, Susana Conde; Dahl, Russell; Dalesandro, David; Delaet, Nancy G. J.; Erb, Eric; Ernst, Justin T.; Gibbs, Andrew R.; Kahl, Jeffrey D.; Kessler, Linda; Lundström, Jan O.; Miller, S.A.; Nakanishi, Hiroshi; Roberts, Edward; Saiah, Eddine; Sullivan, Robert W.; Wang, Zhijun; Larson, Christopher J.

doi:10.1016/j.ejphar.2010.01.011

Cited by 11 publications

(7 citation statements)

References 36 publications

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“…The advantage of such inhibitors lies in the fact that the regulation (mostly down regulation) of p38MAPK activities plays a significant controlling role in many diseases (Figure 4), thereby, targeting a broad range of inflammatory disease pathologies [112–114]. We propose that these inhibitors might provide alleviation and protection against the development of PTB and pPROM.…”

Section: The Importance Of the P38mapk Signaling Pathway To The Dementioning

confidence: 99%

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

Menon¹,

Papaconstantinou²

2016

Expert Opinion on Therapeutic Targets

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Introduction Spontaneous preterm birth (PTB) and preterm premature rupture of the membranes (pPROM) remain as a major clinical and therapeutic problem for intervention and management. Current strategies, based on our knowledge of pathways of preterm labor, have only been effective, in part, due to major gaps in our existing knowledge of risks and risk specific pathways. Areas covered Recent literature has identified physiologic aging of fetal tissues as a potential mechanistic feature of normal parturition. This process is affected by telomere dependent and p38 mitogen activated protein kinase (MAPK) induced senescence activation. Pregnancy associated risk factors can cause pathologic activation of this pathway that can cause oxidative stress induced p38 MAPK activation leading to senescence and premature aging of fetal tissues. Premature aging is associated with sterile inflammation capable of triggering preterm labor or preterm premature rupture of membranes. Preterm activation of p38MAPK can be considered as a key contributor to adverse pregnancies. Expert Opinion This review considers p38MAPK activation as a potential target for therapeutic interventions to prevent adverse pregnancy outcomes mediated by stress factors. In this review, we propose multiple strategies to prevent p38MAPK activation and its functional effects.

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Section: The Importance Of the P38mapk Signaling Pathway To The Dementioning

confidence: 99%

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

Menon¹,

Papaconstantinou²

2016

Expert Opinion on Therapeutic Targets

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show abstract

“…Also, dosing, biodistribution, targeting of the wrong p38 kinase isoforms, and compensatory effects in other kinases that can regulate the same genes have been proposed 25. Nevertheless, upstream inhibition of the p38 MAPK signalling pathway is feasible and efficacious in animal models of arthritis 26. Thus, information regarding safety of p38 inhibition may be relevant if this preclinical information leads to the development of upstream inhibitors of the p38 signalling pathway.…”

Section: Introductionmentioning

confidence: 99%

Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis

et al. 2013

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“…18 Collageninduced arthritis (CIA), a murine model of rheumatoid arthritis, can be substantially inhibited by pharmacologic inhibition of p38␣ and p38␤. 22,23 Given the data demonstrating roles for p38 in autoimmune and inflammatory processes, we asked whether there was a specific contribution made by T-cell p38 activated via TCR occupancy and the alternative pathway. To completely abrogate this pathway, we created p38␤ Y323F knockin mice, which were crossed to p38␣ Y323F mice to generate p38␣␤ Y323F double knockins.…”

Section: Introductionmentioning

confidence: 99%

Lack of the T cell–specific alternative p38 activation pathway reduces autoimmunity and inflammation

Jirmanova

Torchia

Sarma

et al. 2011

Blood

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Stimulation via the T-cell receptor (TCR) activates p38␣ and p38␤ by phosphorylation of p38 Tyr-323 (p38 Y323 ). Here we characterize knockin mice in which p38␣ and/or ␤ Tyr-323 has been replaced with Phe. We find that p38␣ accounts for twothirds and p38␤ the remainder of TCRinduced p38 activation. T cells from double knockin mice (p38␣␤ Y323F ) had defects in TCR-mediated proliferation and Th1 and Th17 skewing, the former corresponding with an inability to sustain T-bet expression. Introduction of p38␣ Y323F into Gadd45␣-deficient mice, in which the alternative p38 pathway is constitutively active, reversed T-cell hyperproliferation and autoimmunity. Furthermore, p38␣␤ Y323F mice had delayed onset and reduced severity of the inflammatory autoimmune diseases collagen-induced arthritis and experimental autoimmune encephalomyelitis. Thus, T cell-specific alternative activation of p38 is an important pathway in T-cell proliferation, Th skewing, and inflammatory autoimmunity, and may be an attractive tissuespecific target for intervention in these processes. (Blood. 2011;118(12):3280-3289)

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KR-003048, a potent, orally active inhibitor of p38 mitogen-activated protein kinase

Cited by 11 publications

References 36 publications

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis

Lack of the T cell–specific alternative p38 activation pathway reduces autoimmunity and inflammation

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