title: 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.
authors.affiliation: Department of Medicine, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, United States; Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Cheminpharma LLC, 23 Business Park Drive, Branford, CT 06405, United States.
authors.forename: Mahendra D
authors.initials: MD
authors.lastname: Chordia
authors.affiliation: AlloMek Therapeutics LLC, 400 Farmington Avenue, Farmington, CT 06032, United States.
authors.forename: Barry P
authors.initials: BP
authors.lastname: Hart
authors.affiliation: Cheminpharma LLC, 23 Business Park Drive, Branford, CT 06405, United States.
authors.forename: E Sathyajith
authors.initials: ES
authors.lastname: Kumarasinghe
authors.affiliation: Cheminpharma LLC, 23 Business Park Drive, Branford, CT 06405, United States.
authors.forename: Min K
authors.initials: MK
authors.lastname: Ji
authors.affiliation: Shakti BioResearch LLC, 1 Bradley Road, Suite 401, Woodbridge, CT 06525, United States.
authors.forename: Ajay
authors.initials: A
authors.lastname: Bhargava
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, United States.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lawlor
authors.affiliation: Department of Medicine, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, United States; Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, United States.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Department of Medicine, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, United States.
authors.forename: Fusako
authors.initials: F
authors.lastname: Sera
authors.affiliation: Department of Medicine, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, United States.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.affiliation: Department of Medicine, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, United States; Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, United States.
authors.forename: Antoine
authors.initials: A
authors.lastname: Muchir
authors.affiliation: Cheminpharma LLC, 23 Business Park Drive, Branford, CT 06405, United States; AlloMek Therapeutics LLC, 400 Farmington Avenue, Farmington, CT 06032, United States. Electronic address: ukhire@allomek.com.
authors.forename: Uday R
authors.initials: UR
authors.lastname: Khire
authors.affiliation: Department of Medicine, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, United States; Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, United States. Electronic address: hjw14@columbia.edu.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D034904:Lamin Type A / Q000235:genetics*; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D034904:Lamin Type A; D047028:Macrocyclic Compounds; D047428:Protein Kinase Inhibitors; D019950:Mitogen-Activated Protein Kinase 1
keywords: Cardiomyopathy; Emery-Dreifuss muscular dystrophy; Extracellular signal-regulated kinase; Lamin; MEK inhibitor; Mitogen-activated protein kinase