Current Topics in Medicinal Chemistry - Volume 17, Issue 24, 2017

Untargeted metabolomics is a promising approach for reducing the significant attrition rate for discovering and developing drugs in the pharmaceutical industry. This review aims to highlight the practical decision-making value of untargeted metabolomics for the advancement of drug candidates in drug discovery/development including potentially identifying and validating novel therapeutic targets, creating alternative screening paradigms, facilitating the selection of specific and translational metabolite biomarkers, identifying metabolite signatures for the drug efficacy mechanism of action, and understanding potential drug-induced toxicity. The review provides an overview of the pharmaceutical process workflow to discover and develop new small molecule drugs followed by the metabolomics process workflow that is involved in conducting metabolomics studies. The pros and cons of the major components of the pharmaceutical and metabolomics workflows are reviewed and discussed. Finally, selected untargeted metabolomics literature examples, from primarily 2010 to 2016, are used to illustrate why, how, and where untargeted metabolomics can be integrated into the drug discovery/preclinical drug development process.

Nowadays, cancer therapy remains limited by the conventional one-size-fits-all approach. In this context, treatment decisions are based on the clinical stage of disease but fail to ascertain the individual ´s underlying biology and its role in driving malignancy. The identification of better therapies for cancer treatment is thus limited by the lack of sufficient data regarding the characterization of specific biochemical signatures associated with each particular cancer patient or group of patients. Metabolomics approaches promise a better understanding of cancer, a disease characterized by significant alterations in bioenergetic metabolism, by identifying changes in the pattern of metabolite expression in addition to changes in the concentration of individual metabolites as well as alterations in biochemical pathways. These approaches hold the potential of identifying novel biomarkers with different clinical applications, including the development of more specific diagnostic methods based on the characterization of metabolic subtypes, the monitoring of currently used cancer therapeutics to evaluate the response and the prognostic outcome with a given therapy, and the evaluation of the mechanisms involved in disease relapse and drug resistance. This review discusses metabolomics applications in different oncological processes underlining the potential of this omics approach to further advance the implementation of precision medicine in the oncology area.

Chronic liver diseases are one of the major causess of mortality worldwide. It can manifest through many different forms including chronic virus infection, alcohol abuse, metabolic syndromes such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. At early stages, the liver can repair the damage produced by the insult. However, upon continuous damage, the accumulation of molecules triggers fibrosis, which subsequently progresses towards cirrhosis and, ultimately, hepatocarcinoma. Early diagnosis of liver disease and a proper staging of fibrosis are crucial in therapy since drugs are only effective at incipient and intermediate stages of the disease. In this context, liver biopsy is the gold standard, but it is invasive and can produce complications. Metabolomics has emerged as a potent discipline to identify new biomarkers in a non-invasive way. Here, we compile and critically review the existing NMR-based metabolomics studies on chronic liver diseases, specifically covering non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic liver disease and those produced by virus infection.

Urinary protein biomarkers and metabolomic markers have been leveraged to detect acute Drug Induced Kidney Injury (DIKI) in rats; however, the utility of these indicators to enable early detection of DIKI in canine models has not been well documented. Therefore, we evaluated temporal changes in biomarkers and metabolites in urine from male and female beagle dogs. Gentamicin- induced kidney lesions in male dogs were characterized by moderate to severe tubular epithelial cell degeneration/necrosis, epithelial cell regeneration and dilation; and a unique urinebased metabolomic fingerprint. These metabolite changes included time and treatment-dependent increases in lactate, taurine, glucose, lactate, alanine, and citrate as well as 9 other known metabolites. As early as 3 days post dose, gentamicin induced increases in urinary albumin, clusterin, neutrophil gelatinase associated protein (NGAL) and total protein concentrations. Urinary albumin, clusterin, and NGAL showed earlier and more robust elevations than traditional kidney safety biomarkers, blood urea nitrogen and serum creatinine. Elevations in urinary kidney injury molecule 1 (KIM-1) were less reliable for detection of gentamicin nephrotoxicity in dogs based on values generated utilizing multiple first-generation, canine-specific KIM-1 immunoassays. The metabolic fingerprint was further evaluated in male and female dogs that received Compound A which induced slightly reversible renal tubular alterations characterized as degeneration/necrosis and concurrent significant increases in urinary taurine amongst other markers. These data support further investigations to demonstrate the value of urinary metabolites, albumin, clusterin, NGAL and taurine as promising markers to enable early detection of DIKI in dogs.

We have developed a workflow to extract, separate, and semi-quantify bioactive oxysterols from mouse colon tissues and fecal matters using solid- and liquid-phase extractions, enzymatic and chemical modifications, and stable-isotope dilution LC/MS/MS. The method was applied to a dextran sodium sulphate (DSS)-induced mouse colitis model, which revealed that one particular dihydroxycholesterol (diOHC), 7α,25-diOHC, was significantly elevated in both colon tissue and fecal matters of mice with colitis compared to that in naïve mice. The extent of 7α,25-diOHC elevation was positively correlated with colitis severity.

We have developed a targeted metabolomics screen which consists of using two isotopically labeled glucose compounds to conduct a dual oral glucose tolerance test in rats. This dual isotopic oral glucose tolerance test (DIS-OGTT) can be used to select drug candidates that have “on”-target or have “off”-target effects on oral glucose absorption, hepatic glucose production or glucose disposal. The DIS-OGTT assay utilized intravenously administered [6-13C1-6, 6'-2H2]-glucose and orally administered [U-13C6] glucose to monitor glucose homeostasis. In the experiment, a constant intravenous dose of [6-13C1-6, 6'-2H2] glucose was converted in vivo to a series of [M+1] glucose isotopomers and unlabeled [M] glucose via gluconeogenesis while the orally administered [U-13C6] glucose was converted to a series of [M+3] and [M+2] glucose isotopomers via gluconeogenesis. The detection platform of the assay was based on a negative mode electrospray ionization liquid chromatography tandem mass spectrometry method where the deprotonated glucose anion and its various isotopomers were quantitated in rat plasma using multiple reaction monitoring techniques. The in vivo rat DIS-OGTT assay was a sensitive method for understanding drug candidates underlying postprandial effects on glucose absorption, hepatic glucose production, and insulin controlled glucose disposal. Since glucose derivatization was not required for this assay, a higher sample throughput DIS-OGTT was achieved.