Pharmacological inhibition of ALDH1A enzymes suppresses weight gain in a mouse model of diet-induced obesity

Haenisch, Michael; Treuting, Piper M.; Brabb, Thea; Goldstein, Alex S.; Berkseth, Kathryn E.; Amory, John K.; Paik, Ji-Sun

doi:10.1016/j.orcp.2017.08.003

Cited by 27 publications

(34 citation statements)

References 19 publications

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“… 11 , 12 Furthermore, increased production of retinoic acid by intestinal CD14 + macrophages associated with local induction of ALDH1A1 expression was shown to contribute to their inflammatory phenotype in Crohn’s disease patients. 13 These findings suggest that inhibition of ALDH1A1 enzymatic activity may offer new therapeutic options not only for cancer but also for obesity, 14 diabetes, and inflammation. As such, discovery of novel small molecule ALDH (e.g., ALDH1A1) inhibitors with suitable drug-like properties and selectivity profiles is a prudent approach for potential new cancer therapeutics and other diseases.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity

et al. 2018

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Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) and possess vital physiological and toxicological functions in areas such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of certain ALDHs (e.g., ALDH1A1) is an important biomarker in cancers and cancer stem cells (CSCs) indicating the potential need for the identification and development of small molecule ALDH inhibitors. Herein, a newly designed series of quinoline-based analogs of ALDH1A1 inhibitors is described. Extensive medicinal chemistry optimization and biological characterization led to the identification of analogs with significantly improved enzymatic and cellular ALDH inhibition. Selected analogs, e.g., 86 (NCT-505) and 91 (NCT-506), demonstrated target engagement in a cellular thermal shift assay (CETSA), inhibited the formation of 3D spheroid cultures of OV-90 cancer cells, and potentiated the cytotoxicity of paclitaxel in SKOV-3-TR, a paclitaxel resistant ovarian cancer cell line. Lead compounds also exhibit high specificity over other ALDH isozymes and unrelated dehydrogenases. The in vitro ADME profiles and pharmacokinetic evaluation of selected analogs are also highlighted.

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Section: Introductionmentioning

confidence: 99%

Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity

et al. 2018

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“…This bioinformatic result, which at first glance appears to be contradictory to the biochemical results regarding an increased glycolytic activity, can be discussed under various aspects: the gene products of the above mentioned genes, such as the alcohol dehydrogenase 1C (ADH1C) and the aldehyde dehydrogenase 1 family member A1 (ALDH1A1), are indirectly associated to glycolysis. Both gene products are involved in alcohol metabolism and the ALDH1A1 is also involved in the regulation of the metabolic response to a high-fat diet [46,47]. In a regulatory context, the protein phosphatase, Mg2+/Mn2+ dependent 1L (PPM1L) is also of interest.…”

Section: Discussionmentioning

confidence: 99%

TGF-ß1 Induces Changes in the Energy Metabolism of White Adipose Tissue-Derived Human Adult Mesenchymal Stem/Stromal Cells In Vitro

et al. 2020

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Adipose tissue plays an active role in the regulation of the body’s energy balance. Mesenchymal stem/stromal cells from adipose tissue (adMSC) are the precursor cells for repair and adipogenesis. Since the balance of the differentiation state of adipose tissue-resident cells is associated with the development of various diseases, the examination of the regulation of proliferation and differentiation of adMSC might provide new therapeutic targets. Transforming growth factor-β1 (TGF-ß1) is synthetized by many cell types and is involved in various biological processes. Here, we investigated the effects of different concentrations of TGF-ß1 (1–10 ng/mL) on adMSC proliferation, metabolic activity, and analyzed the gene expression data obtained from DNA microarrays by bioinformatics. TGF-ß1 induced the concentration- and time-dependent increase in the cell number of adMSC with simultaneously unchanged cell cycle distributions. The basal oxygen consumption rates did not change significantly after TGF-ß1 exposure. However, glycolytic activity was significantly increased. The gene expression analysis identified 3275 differentially expressed genes upon exposure to TGF-ß1. According to the pathway enrichment analyses, they also included genes associated with energy metabolism. Thus, it was shown that TGF-ß1 induces changes in the energy metabolism of adMSC. Whether these effects are of relevance in vivo and whether they contribute to pathogenesis should be addressed in further examinations.

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“…Tissues were homogenized in 25 mM Tris buffer (pH 7.4) containing 0.25 M sucrose, 1 mM DTT with metal lysing matrix beads (MP Biomedicals) and centrifuged at 10,000× g for 15 min. Supernatants containing cytosolic ALDH1A enzymes (S10) were used to determine RA synthesis capacity as previously reported [ 39 ]. Briefly, S10 fractions of liver (15 µg), testis (15 µg) or MLN (30 µg) were incubated with 1 µM retinal and 2 mM NAD for 10 min at 37 °C in an enzyme activity buffer (10 mM HEPES, 150 mM KCl, 2 mM EDTA, pH 7.5).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, S10 fractions of liver (15 µg), testis (15 µg) or MLN (30 µg) were incubated with 1 µM retinal and 2 mM NAD for 10 min at 37 °C in an enzyme activity buffer (10 mM HEPES, 150 mM KCl, 2 mM EDTA, pH 7.5). Enzyme activity was quenched with acetonitrile: methanol (1:1, vol: vol) containing all- trans RA-d5 (internal standard), and supernatants (3500× g , 10 min) were collected to measure RA using LC-MS [ 39 ]. RA synthesis capacity (pmol/µg prot/min) was expressed as % of control (animals treated with vehicle).…”

Section: Methodsmentioning

confidence: 99%

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Protective Effects of ALDH1A Enzyme Inhibition on Helicobacter-Induced Colitis in Smad3−/− Mice are Associated with Altered α4ß7 Integrin Expression on Activated T Cells

et al. 2020

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Many inflammatory bowel disease (IBD) patients require surgical intervention due to limited pharmacological treatment options. Antibodies targeting α4ß7, a gut-homing integrin, are one of the most promising IBD treatments. As retinoic acid (RA) regulates expression of gut-homing proteins including α4ß7 integrin, we tested if ALDH1A enzymes in the RA synthesis pathway could be targeted for IBD treatment using a potent inhibitor, WIN 18,446. Age- and sex-matched Smad3−/− mice were fed a diet with and without WIN 18,446 for 3 weeks before triggering inflammation with Helicobacter bilis infection. Colitis was evaluated by histopathology one week following the IBD trigger, and T cell subsets were evaluated before and after the IBD trigger. WIN 18,446 treatment significantly reduced IBD severity in Smad3−/− mice and reduced expression of α4ß7 integrin on multiple activated CD4+ T cell subsets. This change was associated with increased ratios of induced regulatory T cells to Th17 cells during the inflammatory response in the draining lymph nodes. These studies indicate that RA reduction via ALDH1A enzyme inhibition is a potential new target for IBD treatment. Further studies are needed to examine its effects on other types of immune cells, to evaluate the efficacy window for this target, and to determine its efficacy in other animal models of IBD.

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Pharmacological inhibition of ALDH1A enzymes suppresses weight gain in a mouse model of diet-induced obesity

Abstract: Pharmacological suppression of RA synthesis via inhibition of ALDH1A1 may be a potential target for treatment of obesity.

Cited by 27 publications

References 19 publications

Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity

Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity

TGF-ß1 Induces Changes in the Energy Metabolism of White Adipose Tissue-Derived Human Adult Mesenchymal Stem/Stromal Cells In Vitro

Protective Effects of ALDH1A Enzyme Inhibition on Helicobacter-Induced Colitis in Smad3−/− Mice are Associated with Altered α4ß7 Integrin Expression on Activated T Cells

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