Developing small molecules to inhibit kinases unkind to the heart: p38 MAPK as a case in point

Marber, Michael; Molkentin, Jeffery D.; Force, Thomas

doi:10.1016/j.ddmec.2010.07.006

Cited by 28 publications

(12 citation statements)

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“…In particular, p38 is highly responsive to the ROS elevation seen in I/R (26, 27). Correspondingly, p38 inhibitors are beneficial in numerous models (28, 29), but adverse on- and off-target effects have hampered clinical translation. To address this, recent p38 inhibitor trials propose partial inhibition of the kinase (28), potentially limiting or even precluding therapeutic benefits with more complete inhibition.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K Limits Oxidative Stress, Injury, and Adverse Remodeling in the Ischemic Heart

et al. 2013

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Percutaneous coronary intervention is first-line therapy for acute coronary syndromes (ACS) but can promote cardiomyocyte death and cardiac dysfunction via reperfusion injury, a phenomenon driven in large part by oxidative stress. Therapies to limit this progression have proven elusive, with no major classes of new agents since the development of anti-platelets/anti-thrombotics. We report that cardiac troponin I–interacting kinase (TNNI3K), a cardiomyocyte-specific kinase, promotes ischemia/reperfusion injury, oxidative stress, and myocyte death. TNNI3K-mediated injury occurs through increased mitochondrial superoxide production and impaired mitochondrial function and is largely dependent on p38 mitogen-activated protein kinase (MAPK) activation. We developed a series of small-molecule TNNI3K inhibitors that reduce mitochondrial-derived superoxide generation, p38 activation, and infarct size when delivered at reperfusion to mimic clinical intervention. TNNI3K inhibition also preserves cardiac function and limits chronic adverse remodeling. Our findings demonstrate that TNNI3K modulates reperfusion injury in the ischemic heart and is a tractable therapeutic target for ACS. Pharmacologic TNNI3K inhibition would be cardiac-selective, preventing potential adverse effects of systemic kinase inhibition.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K Limits Oxidative Stress, Injury, and Adverse Remodeling in the Ischemic Heart

et al. 2013

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“…The small molecule inhibitors of p38 have been studied for almost 20 years, predominantly in terms of the anti-inflammatory effect of the inhibitors [80]. However, most of the outcomes of using the p38 inhibitors in clinical trials have been disappointing as a result of adverse events stemming from drug toxicity [81].…”

Section: Reports Of P38 Inhibitors In An In Vivo Model Of Ischemia/rementioning

confidence: 99%

Role of p38 inhibition in cardiac ischemia/reperfusion injury

Kumphune

Chattipakorn

2011

Eur J Clin Pharmacol

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The p38 mitogen-activated protein kinases (p38s) are Ser/Thr kinases that are activated as a result of cellular stresses and various pathological conditions, including myocardial ischemia/reperfusion. p38 activation has been shown to accentuate myocardial injury and impair cardiac function. Inhibition of p38 activation and its activity has been proposed to be cardioprotective by slowing the rate of myocardial damage and improving cardiac function. The growing body of evidence on the use of p38 inhibitors as therapeutic means for responding to heart problems is controversial, since both beneficial as well as a lack of protective effects on the heart have been reported. In this review, the outcomes from studies investigating the effect of p38 inhibitors on the heart in a wide range of study models, including in vitro, ex vivo, and in vivo models, are discussed. The correlations of experimental models with practical clinical usefulness, as well as the need for future studies regarding the use of p38 inhibitors, are also addressed.

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“…57 As a consequence, p38 is one of the most investigated kinases with a wealth of literature in models relevant to cardiovascular disease. 58,59 For the purposes of this review, we focus on those biological processes that underpin myocardial infarction and subsequent remodeling, because it is in this area that current clinical trial activity is focused.…”

Section: Role Of P38 In Cardiovascular Biologymentioning

confidence: 99%