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

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• 作者：Wei Wu^a ; ^b ; Mahendra D. Chordia^c ; ^g ; Barry P. Hart^d ; E. Sathyajith Kumarasinghe^c ; Min K. Ji^c ; Ajay Bhargava^e ; Michael W. Lawlor^f ; Ji-Yeon Shin^a ; ^b ; Fusako Sera^a ; Shunichi Homma^a ; Antoine Muchir^a ; ^b ; ^h ; Uday R. Khire^c ; ^d ; ^{ukhire@allomek.com} ; Howard J. Worman^a ; ^b ; ^{hjw14@columbia.edu}
• 关键词：Cardiomyopathy ; Emery-Dreifuss muscular dystrophy ; Extracellular signal-regulated kinase ; Lamin ; MEK inhibitor ; Mitogen-activated protein kinase
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：1004-1013
• 全文大小：1627 K
• 卷排序：25

文摘

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.