Macrocyclic MEK1/2 inhibitor with efficacy in a mouse model of cardiomyopathy caused by lamin A/C gene mutation

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.

Emery‐Dreifuss muscular dystrophy

“…One therapeutic strategy targets the activation of the mitogen‐activated protein kinase (MAPK) pathway, particularly the extracellular‐signal regulated kinase (ERK) branch . Candidate therapies that inhibit MAPK/ERK activity have included PD98059, selumetinib, “molecule 8”, and the ACE inhibitor benazepril . ARRY‐371797 targets a different branch of the MAPK cascade, p38α, and prevented cardiac complications in a mouse model of laminopathy .…”

Role of Lamin A/C Gene Mutations in the Signaling Defects Leading to Cardiomyopathies

“…In the hearts of Lmna H222P/H222P mice, hyper-activation of ERK1/2, JNK and P38α was reported before the onset of significant cardiac impairments ( Muchir et al, 2007 , 2012a ) likely indicating that MAP kinases hyperactivation is not a consequence but rather a causative event of the cardiac disease. Strikingly, genetic or pharmacological approaches used to control ERK1/2 signaling in Lmna H222P/H222P mice had a positive outcome on cardiac symptoms led to survival prolongation ( Muchir et al, 2012a ; Wu et al, 2011 , 2014 , 2017 ). In addition, several downstream target genes were activated by MAPKs in hearts of Lmna H222P/H222P mice ( Wu et al, 2011 , 2017 ; Muchir et al, 2012a ; Chatzifrangkeskou et al, 2016 ).…”

“…Strikingly, genetic or pharmacological approaches used to control ERK1/2 signaling in Lmna H222P/H222P mice had a positive outcome on cardiac symptoms led to survival prolongation ( Muchir et al, 2012a ; Wu et al, 2011 , 2014 , 2017 ). In addition, several downstream target genes were activated by MAPKs in hearts of Lmna H222P/H222P mice ( Wu et al, 2011 , 2017 ; Muchir et al, 2012a ; Chatzifrangkeskou et al, 2016 ). All these targets might in turn, modulate the expression of additional genes encoding for proteins potentially involved in pathogenic mechanisms of cardiac diseases ( Gillespie-Brown et al, 1995 ; Thorburn et al, 1995 ).…”

Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

“…The pathogenicity of Erk 1/2 activation has been proven in preclinical models. Inhibitors of Erk 1/2 or MEK or other molecules in the signaling pathway have been able to delay the onset of cardiomyopathy in Lmna H222P/H222P mice, which die prematurely due to cardiac impairment [9]. Further, activation of PI3-kinase leading to Akt/mTOR phosphorylation, has been demonstrated in laminopathic mice.…”

“…Further studies will better define the complex molecular mechanism leading to cardiolaminopathies and confirm Erk ½ [9], mTOR [11], TGFbeta 2 [16] betaCatenin [8] or connective tissue growth factor [7] as targets of therapeutic intervention.…”