Uday Khire

Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity

The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.

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

Abstract 736: Novel, potent MEK inhibitor CIP-1374 for the treatment of cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Mitogen-activated protein kinases (MAPKs) are clinically validated, well-established targets for seeking anti-cancer therapy. MAPKs specifically phosphorylate serine/threonine residues of proteins, which are activated by variety of external stimuli (for example mitogens and growth factors) to manifest its actions inside the cell. The activation of MAPKs regulates many functions of the cells with profound physiological implications such as cell growth, survival, apoptosis, differentiation, proliferation and gene expression. MEK 1 and 2 are two human kinases presented in the middle of the classical MAPK-cascade involving upstream RAS-RAF and downstream ERKs. This signal transduction cascade ending in phophorylation of ERKs is extensively studied in cancer pathology. The phosphorylated-ERK upon its translocation to nucleus activates several transcription factors to induce the expression of many genes required for cell survival and proliferation. Because of very high selectivity conferred on MEKs to phophorylate only ERK1 and ERK2, targeting its inhibition offers a very attractive strategy for anti-cancer drug discovery. In addition, the mechanism of action of the known MEK inhibitors such as PD98059 and U0126 is non ATP-competitive (binding to allosteric site) and thus may have least side effects in clinical utility sets in high priority to discover new inhibitors. Currently there are few MEK inhibitors undergoing clinical studies, these includes ARRY-162 (Array Biopharma), RDEA-119 (Ardea biosciences) in combination with sorafenib displaying significant response in sorafenib resistant hepatoma cells and XL-518 (Exelixis) for solid tumors. We present here the discovery of a potent novel MEK inhibitor CIP-1374 for the treatment of cancer. The preliminary in vitro data including inhibition of ERK phophorylation, and whole cell anti-proliferation assays in variety of cancer cell lines will be presented. CIP-1374 exhibited MEK-1 IC50 21.0 nM. In the presence of 1.0 mM ATP, CIP-1374 retained inhibitory activity indicating allosteric mode of binding in ATP non-competitive fashion. The selectivity for MEK inhibition leading to non-proliferation will be presented from the cells without RAS mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 736.