Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase

Panayotis C. Theodoropoulos; Stephen S. Gonzales; Sarah E. Winterton; Carlos Rodriguez-Navas; John S. McKnight; Lorraine K. Morlock; Jordan M. Hanson; Bethany Cross; Amy E. Owen; Yingli Duan; Jose R. Moreno; Andrew Lemoff; Hamid Mirzaei; Bruce A. Posner; Noelle S. Williams; Joseph M. Ready; Deepak Nijhawan

doi:10.1038/nchembio.2016

Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase

Panayotis C. Theodoropoulos, Stephen S. Gonzales, Sarah E. Winterton, Carlos Rodriguez-Navas, John S. McKnight, Lorraine K. Morlock, Jordan M. Hanson, Bethany Cross, Amy E. Owen, Yingli Duan, Jose R. Moreno, Andrew Lemoff, Hamid Mirzaei, Bruce A. Posner, Noelle S. Williams, Joseph M. Ready, Deepak Nijhawan

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

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.

Original language	English (US)
Pages (from-to)	218-225
Number of pages	8
Journal	Nature chemical biology
Volume	12
Issue number	4
DOIs	https://doi.org/10.1038/nchembio.2016
State	Published - Apr 1 2016

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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Theodoropoulos, P. C., Gonzales, S. S., Winterton, S. E., Rodriguez-Navas, C., McKnight, J. S., Morlock, L. K., Hanson, J. M., Cross, B., Owen, A. E., Duan, Y., Moreno, J. R., Lemoff, A., Mirzaei, H., Posner, B. A., Williams, N. S., Ready, J. M., & Nijhawan, D. (2016). Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase. Nature chemical biology, 12(4), 218-225. https://doi.org/10.1038/nchembio.2016

Theodoropoulos, PC, Gonzales, SS, Winterton, SE, Rodriguez-Navas, C, McKnight, JS, Morlock, LK, Hanson, JM, Cross, B, Owen, AE, Duan, Y, Moreno, JR, Lemoff, A, Mirzaei, H, Posner, BA , Williams, NS , Ready, JM & Nijhawan, D 2016, 'Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase', Nature chemical biology, vol. 12, no. 4, pp. 218-225. https://doi.org/10.1038/nchembio.2016

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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.",

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Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase

Abstract

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