Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain l-2-hydroxy acid oxidase

Barawkar, Dinesh A.; Bandyopadhyay, Anish; Deshpande, Anil M.; Koul, Sushma; Kandalkar, Sachin R.; Patil, P N; Khose, Goraksha; Vyas, Samir K.; Mone, Mahesh; Bhosale, Shubhangi; Singh, Umesh; De, Siddhartha; Meru, Ashwin; Gundu, Jayasagar; Chugh, Anita; Palle, Venkata P.; Mookhtiar, Kasim A.; Vacca, Joseph P.; Chakravarty, Prasun K.; Nargund, Ravi P.; Wright, Samuel D.; Roy, Sophie; Graziano, Michael P.; Cully, Doris; Cai, Tian-Quan; Singh, Sheo B.

doi:10.1016/j.bmcl.2012.05.020

Cited by 10 publications

(4 citation statements)

References 15 publications

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“…We also confirm elevated levels of metabolites associated with higher reported alcohol intake from a previous metabolomics study [ 2 ]; in particular, circulating levels of the amino acid alpha-hydroxyisovalerate, the inositol metabolite lipid scyllo-inositol and sulphated steroids derived from dehydroepiandrosterone metabolism (DHEA; 5-alpha-androstan-3beta,17beta-diol disulfate, 4-androsten-3beta,17beta-diol disulfate 1, 5-alpha-androstan-3beta,17beta-diol disulfate and epiandrosterone sulfate) [ 2 ]. Interestingly, alpha-hydroxyisovalerate associates to a variant in the HAO2 gene (rs12141041) encoding long-chain L-2-hydroxy acid oxidase 2 which has been shown to be involved in blood pressure regulation in animal models [ 24 ]. Scyllo-inositol is associated with a variant in the SLC5A11 gene (rs4787294) which encodes a myo- and scyllo-inositol transporting sodium-dependent glucose transporter.…”

Section: Discussionmentioning

confidence: 99%

Characterizing Blood Metabolomics Profiles Associated with Self-Reported Food Intakes in Female Twins

et al. 2016

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Using dietary biomarkers in nutritional epidemiological studies may better capture exposure and improve the level at which diet-disease associations can be established and explored. Here, we aimed to identify and evaluate reproducibility of novel biomarkers of reported habitual food intake using targeted and non-targeted metabolomic blood profiling in a large twin cohort. Reported intakes of 71 food groups, determined by FFQ, were assessed against 601 fasting blood metabolites in over 3500 adult female twins from the TwinsUK cohort. For each metabolite, linear regression analysis was undertaken in the discovery group (excluding MZ twin pairs discordant [≥1 SD apart] for food group intake) with each food group as a predictor adjusting for age, batch effects, BMI, family relatedness and multiple testing (1.17x10-6 = 0.05/[71 food groups x 601 detected metabolites]). Significant results were then replicated (non-targeted: P<0.05; targeted: same direction) in the MZ discordant twin group and results from both analyses meta-analyzed. We identified and replicated 180 significant associations with 39 food groups (P<1.17x10-6), overall consisting of 106 different metabolites (74 known and 32 unknown), including 73 novel associations. In particular we identified trans-4-hydroxyproline as a potential marker of red meat intake (0.075[0.009]; P = 1.08x10-17), ergothioneine as a marker of mushroom consumption (0.181[0.019]; P = 5.93x10-22), and three potential markers of fruit consumption (top association: apple and pears): including metabolites derived from gut bacterial transformation of phenolic compounds, 3-phenylpropionate (0.024[0.004]; P = 1.24x10-8) and indolepropionate (0.026[0.004]; P = 2.39x10-9), and threitol (0.033[0.003]; P = 1.69x10-21). With the largest nutritional metabolomics dataset to date, we have identified 73 novel candidate biomarkers of food intake for potential use in nutritional epidemiological studies. We compiled our findings into the DietMetab database (http://www.twinsuk.ac.uk/dietmetab-data/), an online tool to investigate our top associations.

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Section: Discussionmentioning

confidence: 99%

Characterizing Blood Metabolomics Profiles Associated with Self-Reported Food Intakes in Female Twins

et al. 2016

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“…In humans, there are three 2-hydroxy acid oxidase genes named HAO1, HAO2, and HAO3 (also known as HAOX1, HAOX2 and HAOX3), which encode peroxisomal proteins with 2-hydroxy acid oxidase activity [1]. All the members of the hydroxy oxidase family are highly conserved; human HAO2 shares $50% identity with human HAO1 and 72-74% identity with rodent (rat and mouse) Hao2 [2]. HAO2 is predominantly expressed in the liver and kidney, and shows greatest enzymatic activity for long chain 2-hydroxy acid substrates.…”

Section: Introductionmentioning

confidence: 99%

The metabolic gene HAO2 is downregulated in hepatocellular carcinoma and predicts metastasis and poor survival

Mattu

Fornari

Quagliata

et al. 2016

Journal of Hepatology

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Our work identifies for the first time the oncosuppressive role of the metabolic gene Hao2. Indeed, its expression is severely decreased in HCC of different species and etiology, and its reintroduction in HCC cells profoundly impairs tumorigenesis. We also demonstrate that dysregulation of HAO2 is a very early event in the development of HCC and it may represent a useful diagnostic and prognostic marker for human HCC.

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“…Currently, the only approved therapeutic modality for hHAO1 inhibition is RNAi. Existing small molecules in development include chemical series of pyrazole ( Barawkar et al, 2012 ; Chen et al, 2012 ; Bourhis et al, 2009 ), triazole ( Stenberg and Lindqvist 1997 ; Murray et al, 2008 ), or salicylate ( Moya-Garzón et al, 2018 ) backbones and generally consist of a carboxylic acid like moiety mimicking the substrate carboxylic acid and one or more heterocyclic rings that pi stack with FMN (recently reviewed by ( Moya-Garzon et al, 2021 )).…”

Section: Discussionmentioning

confidence: 99%

“…Fragment 1 and its derivatives ( 4 , 7 , 8 ) are superficially similar to published pyrazole inhibitors in structure except that, instead of a carboxylic acid, they contain a carboxamide ( 1 ), methyl-carboxamide ( 4 ), hydroxy-carboxamide ( 7 ), or aminoethyl-carboxamide ( 8 ) group as part of the polar head group and the hydrophobic moiety is a phenyl ring fused to the pyrazole. Exploration of similar rLCHAO inhibitors showed no activity upon similar modification of the pyrazole ring and a 5-fold reduction in potency with a carboxamide ( Barawkar et al, 2012 ), which may explain why carboxamide derivatives of hHAO1 inhibitors have not previously been explored despite the potential improvements in metabolic stability, cellular toxicity and permeability relative to the current carboxylic acid-containing compounds ( Ballatore, Huryn, and Smith 2013 ). This work, however, demonstrates carboxamide derivatives can serve as highly efficient starting points for hHAO1 inhibitor development.…”

Section: Discussionmentioning

confidence: 99%

Novel Starting Points for Human Glycolate Oxidase Inhibitors, Revealed by Crystallography-Based Fragment Screening

et al. 2022

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Primary hyperoxaluria type I (PH1) is caused by AGXT gene mutations that decrease the functional activity of alanine:glyoxylate aminotransferase. A build-up of the enzyme’s substrate, glyoxylate, results in excessive deposition of calcium oxalate crystals in the renal tract, leading to debilitating renal failure. Oxidation of glycolate by glycolate oxidase (or hydroxy acid oxidase 1, HAO1) is a major cellular source of glyoxylate, and siRNA studies have shown phenotypic rescue of PH1 by the knockdown of HAO1, representing a promising inhibitor target. Here, we report the discovery and optimization of six low-molecular-weight fragments, identified by crystallography-based fragment screening, that bind to two different sites on the HAO1 structure: at the active site and an allosteric pocket above the active site. The active site fragments expand known scaffolds for substrate-mimetic inhibitors to include more chemically attractive molecules. The allosteric fragments represent the first report of non-orthosteric inhibition of any hydroxy acid oxidase and hold significant promise for improving inhibitor selectivity. The fragment hits were verified to bind and inhibit HAO1 in solution by fluorescence-based activity assay and surface plasmon resonance. Further optimization cycle by crystallography and biophysical assays have generated two hit compounds of micromolar (44 and 158 µM) potency that do not compete with the substrate and provide attractive starting points for the development of potent and selective HAO1 inhibitors.

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Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain l-2-hydroxy acid oxidase

Cited by 10 publications

References 15 publications

Characterizing Blood Metabolomics Profiles Associated with Self-Reported Food Intakes in Female Twins

Characterizing Blood Metabolomics Profiles Associated with Self-Reported Food Intakes in Female Twins

The metabolic gene HAO2 is downregulated in hepatocellular carcinoma and predicts metastasis and poor survival

Novel Starting Points for Human Glycolate Oxidase Inhibitors, Revealed by Crystallography-Based Fragment Screening

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