Barry Hart

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

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.

Abstract 5470: Potent MEK inhibitor CIP-137401: Preclinical studies

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL In recent years there is a lot of interest in both pre-clinical and clinical setting for the development of MEK kinase inhibitors as therapeutic agents for various cancers. A quite few number of MEK kianse inhibitors are currently undergoing phase I/II clinical trials both as a single agent as well as a combination with variety of other anti-tumor agents. These single agents include AZD-6244, RDEA-119, GSK-1120212, AS-703026 etc. One of the factors favoring MEK kinase as a sought after target besides being a part of very relevant Ras-Raf-MEK-ERK pathway is the identification of an allosteric binding site, which provides excellent selectivity for MEK kinase inhibitors as a class. Constitutive activation of Ras-Raf-MEK-ERK pathway has been a hallmark in several cancer types, including pancreatic, colon, lung, and melanoma. MEK is selective in phosphorylating serine/threonine residues of proteins resulting in regulation of variety of physiological functions of the cell including apoptosis, differentiation, proliferation and gene expression. We recently discovered a novel, potent, non-ATP competitive, allosteric class of MEK kinase inhibitors. Our lead compound, CIP-1374, in the preliminary in vitro data that include primary enzyme assay, inhibition of ERK phophorylation, and anti-proliferation assays in various cell lines exhibited very potent activity. CIP-1374 also displayed excellent pharmaco-kinetic profile in mice with about 17h of half life with about 30% oral bioavailability. Another molecule in this series, CIP-137401 is also displaying a potent in vitro activity in various assays. We are currently focusing on CIP-137401 as our lead candidate and conducting preclinical studies. In this poster, our results in preclinical studies including rat pharmaco-kinetic, metabolic stability, and in-vitro toxicology data will be presented. The in vitro toxicology assays include its profiling in cardiac toxicity data (hERG channel activation). In addition the efficacy data from in vivo tumor xenograft models will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5470. doi:10.1158/1538-7445.AM2011-5470