Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase

Two chemical series, oxalamides and benozothiazoles, produced toxicity in particular lung cancer cells. These compounds were metabolized in these sensitive cells by the cytochrome P450 enzyme CYP4F11 into potent inhibitors of stearoyl CoA desaturase. A hallmark of targeted cancer therapies is select...

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Bibliographic Details
Published in:	Nature chemical biology Vol. 12; no. 4; pp. 218 - 225
Main Authors:	Theodoropoulos, Panayotis C, Gonzales, Stephen S, Winterton, Sarah E, Rodriguez-Navas, Carlos, McKnight, John S, Morlock, Lorraine K, Hanson, Jordan M, Cross, Bethany, Owen, Amy E, Duan, Yingli, Moreno, Jose R, Lemoff, Andrew, Mirzaei, Hamid, Posner, Bruce A, Williams, Noelle S, Ready, Joseph M, Nijhawan, Deepak
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-04-2016 Nature Publishing Group
Subjects:	13/106 631/154/555 631/67/1059 631/92/609 631/92/613 64/60 82/29 82/83 96/98 Animals Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Antineoplastic Agents - toxicity Benzothiazoles - pharmacokinetics Benzothiazoles - pharmacology Benzothiazoles - therapeutic use Benzothiazoles - toxicity Biochemical Engineering Biochemistry Bioorganic Chemistry Cancer Cancer therapies Cell Biology Cell Line, Tumor Chemistry Chemistry/Food Science Cytochrome Cytochrome P-450 Enzyme System - metabolism Cytochrome P450 Family 4 Drug Discovery - methods Female Humans Inhibitors Lung cancer Lung Neoplasms - enzymology Lung Neoplasms - pathology Male Metabolic disorders Metabolism Mice Mice, SCID Molecular Structure Molecular Targeted Therapy Oxamic Acid - analogs & derivatives Oxamic Acid - pharmacokinetics Oxamic Acid - pharmacology Oxamic Acid - therapeutic use Oxamic Acid - toxicity Protein Binding Sebaceous Glands - drug effects Sebaceous Glands - enzymology Sebaceous Glands - pathology Stearoyl-CoA Desaturase - antagonists & inhibitors Toxicity Xenograft Model Antitumor Assays
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Summary:	Two chemical series, oxalamides and benozothiazoles, produced toxicity in particular lung cancer cells. These compounds were metabolized in these sensitive cells by the cytochrome P450 enzyme CYP4F11 into potent inhibitors of stearoyl CoA desaturase. 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.
Bibliography:	These authors contributed equally to this work
ISSN:	1552-4450 1552-4469
DOI:	10.1038/nchembio.2016