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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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).
The authors declare no competing financial interests.
Supplementary Results, Supplementary Tables 1–5, Supplementary Figures 1–6 and Supplementary Note (Synthetic Procedures) (PDF 19570 kb)
Calculation of S scores from the viability of 12 different NSCLC cell lines and HBEC30KT cell line after treatment with 15,483 small molecules. (XLSX 2277 kb)
520 small molecules with chemical structure with accompanying toxicity data in 12 NSCLC cell lines and HBEC30KT along with S scores. (XLSX 3190 kb)
Tandem mass spectrometry results from p37 and p30 excised bands. (XLSX 69 kb)
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Theodoropoulos, P., Gonzales, S., Winterton, S. et al. Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase. Nat Chem Biol 12, 218–225 (2016). https://doi.org/10.1038/nchembio.2016
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