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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Antineoplastic Agents / toxicity
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Benzothiazoles / pharmacokinetics
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Benzothiazoles / pharmacology*
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Benzothiazoles / therapeutic use
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Benzothiazoles / toxicity
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Cell Line, Tumor
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Cytochrome P-450 Enzyme System / metabolism
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Cytochrome P450 Family 4
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Drug Discovery / methods*
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Female
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Humans
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Lung Neoplasms / enzymology*
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Lung Neoplasms / pathology
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Male
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Mice
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Mice, SCID
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Molecular Structure
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Molecular Targeted Therapy
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Oxamic Acid / analogs & derivatives*
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Oxamic Acid / pharmacokinetics
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Oxamic Acid / pharmacology
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Oxamic Acid / therapeutic use
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Oxamic Acid / toxicity
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Protein Binding
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Sebaceous Glands / drug effects
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Sebaceous Glands / enzymology
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Sebaceous Glands / pathology
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Stearoyl-CoA Desaturase / antagonists & inhibitors*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Benzothiazoles
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Cytochrome P-450 Enzyme System
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Cytochrome P450 Family 4
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CYP4F11 protein, human
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Stearoyl-CoA Desaturase
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Oxamic Acid
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oxamide
Associated data
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PubChem-Substance/291368540
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PubChem-Substance/291368541
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PubChem-Substance/291368542
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PubChem-Substance/291368543
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PubChem-Substance/291368544
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PubChem-Substance/291368545
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PubChem-Substance/291368546
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PubChem-Substance/291368547
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PubChem-Substance/291368548
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PubChem-Substance/291368549
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PubChem-Substance/291368550
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PubChem-Substance/291368551
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PubChem-Substance/291368552
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PubChem-Substance/291368553
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PubChem-Substance/291368554
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PubChem-Substance/291368555
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PubChem-Substance/291368556
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PubChem-Substance/291368557
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PubChem-Substance/291368558
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PubChem-Substance/291368559
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PubChem-Substance/291368560
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PubChem-Substance/291368561
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PubChem-Substance/291368562
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PubChem-Substance/291368563
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PubChem-Substance/291368564
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PubChem-Substance/291368565
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PubChem-Substance/291368566
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PubChem-Substance/291368567
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PubChem-Substance/291368568
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PubChem-Substance/291368569
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PubChem-Substance/291368570
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PubChem-Substance/291368571
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PubChem-Substance/291368572
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PubChem-Substance/291368573
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PubChem-Substance/291368574
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PubChem-Substance/291368575
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PubChem-Substance/291368576
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PubChem-Substance/291368577
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PubChem-Substance/291368578
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PubChem-Substance/291368579
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PubChem-Substance/291368580
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PubChem-Substance/291368581
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PubChem-Substance/291368582
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PubChem-Substance/291368583
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PubChem-Substance/291368584
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PubChem-Substance/291368585