Cardiomyopathy is an anatomic and pathologic condition associated with muscle and electrical dysfunction of the heart, usually with inappropriate ventricular hypertrophy or dilatation. There are various causes of cardiomyopathy, many of which are genetic. Dilated cardiomyopathy, the most common form, is characterized by an increase in both myocardial mass and volume. There is no definitive, curative treatment. Research performed at Columbia University has revealed that abnormal activation of the extracellular signal-regulated 1/2 (ERK1/2) branch of the mitogen-activated protein kinase (MAPK) cascade occurs in hearts of Lmna H222P knock-in mice, a model of inherited dilated cardiomyopathy caused by mutation in the lamin A/C gene, which is responsible for about 8% of inherited dilated cardiomyopathies in humans. The research at Columbia has further shown that inhibitors of MAPK/ERK kinase1/2 (MEK1/2), the enzyme that activates ERK1/2, prevent ventricular dilatation, improve cardiac contractility and delay the development of fibrosis in Lmna H222P mice. The goal of the present Small Business Technology Transfer grant proposal is to develop and commercialize this discovery made at Columbia into a treatment for human patients with cardiomyopathy caused by lamin A/C gene mutation. The project is a collaborative effort between Cheminpharma LLC, which has invented and synthesized a proprietary and potent MEK1/2 inhibitor, and the scientists at Columbia who made the initial discoveries.
Aim 1 is to test Cheminpharma's novel MEK1/2 inhibitor, CIP-137401, in the Lmna H222P mouse model of dilated cardiomyopathy.
Aim 2 is to carry out a synthetic route of CIP-137401 to allow for the efficient synthesis of material to support IND enabling studies. This proposal will identif a proprietary MEK1/2 inhibitor with in vivo activity that could be suitable for clinical developmen to treat patients with inherited dilated cardiomyopathy.

Public Health Relevance

Cardiomyopathy is a life-threatening disease that leads to heart failure and death for which there is currently no curative treatment. This project is designed to develop and commercialize a novel drug known as a MEK1/2 inhibitor to treat cardiomyopathy, initially focusing on a specific inherited type.

National Institute of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
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Special Emphasis Panel (ZRG1-CVRS-N (10))
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Brooks, Pj
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Cheminpharma, LLC
New Haven
United States
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Worman, Howard J (2018) Cell signaling abnormalities in cardiomyopathy caused by lamin A/C gene mutations. Biochem Soc Trans 46:37-42
Wu, Wei; Chordia, Mahendra D; Hart, Barry P et al. (2017) Macrocyclic MEK1/2 inhibitor with efficacy in a mouse model of cardiomyopathy caused by lamin A/C gene mutation. Bioorg Med Chem 25:1004-1013
Worman, Howard J; Dauer, William T (2014) The nuclear envelope: an intriguing focal point for neurogenetic disease. Neurotherapeutics 11:764-72