ArticleBioorganic & medicinal chemistry2017
Macrocyclic MEK1/2 inhibitor with efficacy in a mouse model of cardiomyopathy caused by lamin A/C gene mutation.
Article in Bioorganic & medicinal chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 21 citations in OpenAlex.
- LMNA-related cardiomyopathy: From molecular pathology to cardiac gene therapy.Journal of advanced research · 2025Review
- Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations.Nature communications · 2022Article
- Preclinical Advances of Therapies for Laminopathies.Journal of clinical medicine · 2021Review
- Role ofBiomolecules · 2021Article
- Ryanodine receptor remodeling in cardiomyopathy and muscular dystrophy caused by lamin A/C gene mutation.Human molecular genetics · 2021Article
- Emery-Dreifuss muscular dystrophy.Muscle & nerve · 2020Review
- Extracellular signal-regulated kinases 1 and 2 regulate neuromuscular junction and myofiber phenotypes in mammalian skeletal muscle.Neuroscience letters · 2020Review
- Emery-Dreifuss muscular dystrophy: focal point nuclear envelope.Current opinion in neurology · 2019Review
- Cofilin-1 phosphorylation catalyzed by ERK1/2 alters cardiac actin dynamics in dilated cardiomyopathy caused by lamin A/C gene mutation.Human molecular genetics · 2018Article
- Elevated dual specificity protein phosphatase 4 in cardiomyopathy caused by lamin A/C gene mutation is primarily ERK1/2-dependent and its depletion improves cardiac function and survival.Human molecular genetics · 2018Article
- Lamins and Lamin-Associated Proteins in Gastrointestinal Health and Disease.Gastroenterology · 2018Review
- Cell signaling abnormalities in cardiomyopathy caused by lamin A/C gene mutations.Biochemical Society transactions · 2018Review
- Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes.Nucleus (Austin, Tex.) · 2018Review
- Role of Lamin A/C Gene Mutations in the Signaling Defects Leading to Cardiomyopathies.Frontiers in physiology · 2018Review
- The Pathogenesis and Therapies of Striated Muscle Laminopathies.Frontiers in physiology · 2018Review
- Mechanotransduction, nuclear architecture and epigenetics in Emery Dreifuss Muscular Dystrophy: tous pour un, un pour tous.Nucleus (Austin, Tex.) · 2018Review
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
Signaling mediated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) is involved in numerous cellular processes. Mitogen-activated protein kinase kinases (MEK1/2) catalyze the phosphorylation of ERK1/2, converting it into an active kinase that regulates the expression of numerous genes and cellular processes. Inhibitors of MEK1/2 have demonstrated preclinical and clinical efficacy in certain cancers and types of cardiomyopathy. We report the synthesis of a novel, allosteric, macrocyclic MEK1/2 inhibitor that potently inhibits ERK1/2 activity in cultured cells and tissues of mice after systemic administration. Mice with dilated cardiomyopathy caused by a lamin A/C gene mutation have abnormally increased cardiac ERK1/2 activity. In these mice, this novel MEK1/2 inhibitor is well tolerated, improves left ventricular systolic function, decreases left ventricular fibrosis, has beneficial effects on skeletal muscle structure and pathology and prolongs survival. The novel MEK1/2 inhibitor described herein may therefore find clinical utility in the treatment of this rare cardiomyopathy, other types of cardiomyopathy and cancers in humans.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.