Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase
Open Access
- 1 February 2016
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Chemical Biology
- Vol. 12 (4), 218-225
- https://doi.org/10.1038/nchembio.2016
Abstract
A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic at low nanomolar concentrations to the same 4 of 12 human lung cancer cell lines. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible inhibitors of stearoyl CoA desaturase (SCD). SCD is recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes did not activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.Keywords
This publication has 47 references indexed in Scilit:
- Discovery of Piperazin-1-ylpyridazine-Based Potent and Selective Stearoyl-CoA Desaturase-1 Inhibitors for the Treatment of Obesity and Metabolic SyndromeJournal of Medicinal Chemistry, 2012
- The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics DataCancer Discovery, 2012
- The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivityNature, 2012
- SCD1 Inhibition Causes Cancer Cell Death by Depleting Mono-Unsaturated Fatty AcidsPLOS ONE, 2012
- High sensitivity quantitative lipidomics analysis of fatty acids in biological samples by gas chromatography–mass spectrometryBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2011
- Cancer Cell Dependence on Unsaturated Fatty Acids Implicates Stearoyl-CoA Desaturase as a Target for Cancer TherapyMolecular Cancer Research, 2011
- Inhibition of StearoylCoA Desaturase Activity Blocks Cell Cycle Progression and Induces Programmed Cell Death in Lung Cancer CellsPLOS ONE, 2010
- Biochemical and physiological function of stearoyl-CoA desaturaseAmerican Journal of Physiology-Endocrinology and Metabolism, 2009
- Desaturases: Emerging Models for Understanding Functional Diversification of Diiron-containing EnzymesOnline Journal of Public Health Informatics, 2009
- Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometryNature Methods, 2007