TY - JOUR
T1 - Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase
AU - Theodoropoulos, Panayotis C.
AU - Gonzales, Stephen S.
AU - Winterton, Sarah E.
AU - Rodriguez-Navas, Carlos
AU - McKnight, John S.
AU - Morlock, Lorraine K.
AU - Hanson, Jordan M.
AU - Cross, Bethany
AU - Owen, Amy E.
AU - Duan, Yingli
AU - Moreno, Jose R.
AU - Lemoff, Andrew
AU - Mirzaei, Hamid
AU - Posner, Bruce A.
AU - Williams, Noelle S.
AU - Ready, Joseph M.
AU - Nijhawan, Deepak
N1 - Funding Information:
We thank S. Yadavalli and D.C. Trudgian for advice on proteomics, D.W. Russell for guidance on biochemical assays of sebaceous glands and preputial gland dissection, J.G. McDonald and M. Mitsche for advice on fatty acid flux analyses, and S.L. McKnight for helpful discussions and suggestions on the manuscript. C.R.-N. acknowledges the Clayton Foundation for Research and US National Institutes of Health grant HL20948 for support. H.M. acknowledges the Cancer Prevention Research Institute of Texas (CPRIT; RP120613) for funding. B.A.P. acknowledges the Simmons Cancer Center (National Cancer Institute 1P30CA142543-01), CPRIT (RP110708-C2) and CTD2 (1 U01 CA176284-01) for funding. N.S.W. acknowledges CPRIT (RP110708-C3) for funding. J.M.R. acknowledges CPRIT (RP110708-P3) and the Welch Foundation (I-1612) for funding. D.N. acknowledges the Disease Oriented Clinical Scholar (DOCS) award, the Presidential Research Council (PRC) award, the Welch Foundation (I-1879) and the Damon Runyon Clinical Investigator Award (CI-68-13).
Publisher Copyright:
© 2016 Nature America, Inc. All rights reserved.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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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U2 - 10.1038/nchembio.2016
DO - 10.1038/nchembio.2016
M3 - Article
C2 - 26829472
AN - SCOPUS:84961411904
SN - 1552-4450
VL - 12
SP - 218
EP - 225
JO - Nature chemical biology
JF - Nature chemical biology
IS - 4
ER -