Potent, orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors

Koltun, Dmitry O.; Zilbershtein, Timur M.; Migulin, Vasily A.; Vasilevich, Natalya I.; Parkhill, Eric Q.; Glushkov, Andrei I.; McGregor, Malcolm J.; Brunn, Sandra A.; Chu, Nancy; Hao, Jia; Mollova, Nevena; Leung, Kwan; Chisholm, Jeffrey W.; Zablocki, Jeff

doi:10.1016/j.bmcl.2009.06.017

Cited by 29 publications

(14 citation statements)

References 25 publications

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“…Proliferation arrest was partially rescued by supplementing the media with FAs and/or cholesterol, indicating that the ACLY knockdown-mediated growth arrest is the result of either FAs or cholesterol starvation or both [148]. Potent and specific small molecule inhibitors of SCD1 activity, such as BZ36, showed anticancer activity both in vitro and in vivo models [73, 149, 150]. Knockdown of the FA synthesis rate-limiting enzyme ACCα by RNAi leads to inhibition of cell proliferation and induction of caspase-mediated apoptosis in highly lipogenic LNCaP cells.…”

Section: Interfering With Lipid Metabolism As a Therapeutic Approachmentioning

confidence: 99%

The fat side of prostate cancer

Zadra

Photopoulos

Loda

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

239

268

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Prostate cancer (PCa) metabolism appears to be unique in comparison with other type of solid cancers. Normal prostate cells mainly rely on glucose oxidation to provide precursors for the synthesis and secretion of citrate, resulting in an incomplete Krebs cycle and minimal oxidative phosphorylation for energy production. In contrast, during transformation, PCa cells no longer secrete citrate and they reactivate the Krebs cycle as energy source. Moreover, primary PCas do not show increased aerobic glycolysis and therefore they are not efficiently detectable with 18F-FDG-PET. However, increased de novo lipid synthesis, strictly intertwined with deregulation in classical oncogenes and oncosuppressors, is an early event of the disease. Up-regulation and increased activity of lipogenic enzymes (including fatty acid synthase and choline kinase) occurs throughout PCa carcinogenesis and correlates with worse prognosis and poor survival. Thus, lipid precursors such as acetate and choline have been successfully used as alternative tracers for PET imaging. Lipid synthesis intermediates and FA catabolism also emerged as important players in PCa maintenance. Finally, epidemiologic studies suggested that systemic metabolic disorders including obesity, metabolic syndrome, and diabetes as well as hypercaloric and fat-rich diets might increase the risk of PCa. However, how metabolic disorders contribute to PCa development and whether dietary lipids and de novo lipids synthesized intra-tumor are differentially metabolized still remains unclear. In this review, we examine the switch in lipid metabolism supporting the development and progression of PCa and we discuss how we can exploit its lipogenic nature for therapeutic and diagnostic purposes.

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Section: Interfering With Lipid Metabolism As a Therapeutic Approachmentioning

confidence: 99%

The fat side of prostate cancer

Zadra

Photopoulos

Loda

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

239

268

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“…For example, CYB5 is an electron-transporting heme protein of the ER that co-localizes with Δ5, Δ6, and Δ9 desaturases 36, 37 . These enzymes, in coordination with elongases, are required for the biosynthesis of long-chain PUFAs 38 .…”

Section: Discussionmentioning

confidence: 99%

Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice

Miraldi¹,

Sharfi²,

Friedline³

et al. 2013

Integr. Biol.

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Metabolic syndrome describes a set of obesity-related disorders that increase diabetes, cardiovascular, and mortality risk. Studies of liver-specific protein-tyrosine phosphatase 1b (PTP1b) deletion mice (L-PTP1b−/−) suggest that hepatic PTP1b inhibition would mitigate metabolic-syndrome through amelioration of hepatic insulin resistance, endoplasmic-reticulum stress, and whole-body lipid metabolism. However, the altered molecular-network states underlying these phenotypes are poorly understood. We used mass spectrometry to quantitfy protein-phosphotyrosine network changes in L-PTP1b−/− mouse livers relative to control mice on normal and high-fat diets. We applied a phosphosite-set-enrichment analysis to identify known and novel pathways exhibiting PTP1b- and diet-dependent phosphotyrosine regulation. Detection of a PTP1b-dependent, but functionally uncharacterized, set of phosphosites on lipid-metabolic proteins motivated global lipidomic analyses that revealed altered polyunsaturated-fatty-acid (PUFA) and triglyceride metabolism in L-PTP1b−/− mice. To connect phosphosites and lipid measurements in a unified model, we developed a multivariate-regression framework, which accounts for measurement noise and systematically missing proteomics data. This analysis resulted in quantitative models that predict roles for phosphoproteins involved in oxidation-reduction in altered PUFA and triglyceride metabolism.

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“…In one extreme case, the liver concentration is 76-fold higher than that of plasma. 66 Even in those situations, no clear separation of efficacy and adverse effects has been documented. In some cases, much shorter duration of treatment has obscured the interpretation of the pharmacological results.…”

Section: Passively Liver Selective Inhibitorsmentioning

confidence: 99%

“…65 Merging select structural features of the two series led to the discovery of compound 21 (CVT-12,012), which is highly potent in a human cell-based (HEPG2) SCD assay (IC 50 5 6 nM). 66 This compound has 78% oral bioavailability in rats and is preferentially distributed into liver (76 times versus plasma). In a 5-day study with sucrose-fed rats, compound 21 significantly reduced SCD activity, as measured by the DI lowering of the total lipid in a dose-dependent manner in plasma and liver (5, 10, 20 mg/kg), Table 9.3 Thiazole carboxamides and related analogs.…”

Section: Pteridinones and Related Analogsmentioning

confidence: 99%

Chapter 9. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver

Liu¹

2012

Drug Discovery

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Potent, orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors

Cited by 29 publications

References 25 publications

The fat side of prostate cancer

The fat side of prostate cancer

Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice

Chapter 9. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver

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