title: CMX-2043 Mechanisms of Action In Vitro.
abstract: α-Lipoic acid has been shown to provide cytoprotection in some tissues through antioxidant and antiapoptotic mechanisms. We have enhanced these properties by synthetic modification, resulting in a new chemical entity, CMX-2043, with proven efficacy in an animal model of cardiac ischemia-reperfusion injury. The present studies compare cytoprotective cellular pathways of R-α-lipoic acid and CMX-2043. Biochemical and cellular assays were used to compare antioxidant potency, tyrosine kinase activation, and protein kinase B (Akt) phosphorylation. CMX-2043 was more effective than lipoic acid in antioxidant effect, activation of insulin receptor kinase, soluble tyrosine kinase, and Akt phosphorylation. Activation of insulin-like growth factor 1 receptor was similar for both. CMX-2043 stimulation of Akt phosphorylation was abolished by the phosphatidylinositide 3-kinase inhibitor LY294002. Consistent with Akt activation, CMX-2043 reduced carbachol-induced calcium overload. The S-stereoisomer of CMX-2043 was less active in the biochemical assays than the R-isomer. These results are consistent with cytoprotection through activation of Akt and antioxidant action. CMX-2043 may thus provide a pharmacological approach to cytoprotection consistent with established anti-apoptotic mechanisms.
authors.affiliation: Ischemix, LLC, Maynard, MA.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Lader
authors.forename: Alexander
authors.initials: A
authors.lastname: Baguisi
authors.forename: Ralph
authors.initials: R
authors.lastname: Casale
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kates
authors.forename: Reinier
authors.initials: R
authors.lastname: Beeuwkes
mesh_terms: D000072283:A549 Cells; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology*; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D004151:Dipeptides; D020536:Enzyme Activators; C000602148:alpha-N-(1,2-dithiolane-3-pentanoyl)glutamylalanine; D008063:Thioctic Acid; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium