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Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase

Nature Chemical Biology volume 12, pages 218–225 (2016)Cite this article

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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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Figure 1: Oxalamides and benzothiazoles are selective toxins identified in a high-throughput small-molecule phenotypic screen that target the same proteins.
Figure 2: SCD is the target of the oxalamides and the benzothiazoles.
Figure 3: Known SCD inhibitors are nonselectively toxic to cancer cell lines whereas oxalamides are selectively toxic.
Figure 4: Oxalamides are selectively metabolized in sensitive cells to a nonselective SCD inhibitor.
Figure 5: Cytochrome P450 4F11 (CYP4F11) is responsible for oxalamide activation in sensitive cell lines and it is not expressed in insensitive cell lines.
Figure 6: CYP-activated SCD inhibitors are not activated by sebaceous glands and display a therapeutic window to avoid sebaceous gland toxicity compared to known SCD inhibitors.

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Acknowledgements

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).

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  1. Panayotis C Theodoropoulos and Stephen S Gonzales: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA

    Panayotis C Theodoropoulos, Stephen S Gonzales, Sarah E Winterton, Lorraine K Morlock, Jordan M Hanson, Bethany Cross, Jose R Moreno, Andrew Lemoff, Hamid Mirzaei, Bruce A Posner, Noelle S Williams, Joseph M Ready & Deepak Nijhawan

  2. Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, Texas, USA

    Carlos Rodriguez-Navas

  3. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA

    John S McKnight, Amy E Owen, Yingli Duan & Deepak Nijhawan

  4. Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA

    Hamid Mirzaei, Bruce A Posner, Noelle S Williams, Joseph M Ready & Deepak Nijhawan

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Contributions

P.C.T. designed and performed target identification, compound selectivity, compound toxicity studies and wrote the manuscript; S.S.G. synthesized all of the benzothiazoles in the optimization that led to SW203668, Xenon-45, Alexa Fluor dye azide and dMe-SW208108; S.E.W. synthesized all of the oxalamides in the optimization that led to SW208108; C.R.-N. performed fatty acid flux analysis; J.S.M. performed molecular cloning; L.K.M., J.M.H. and B.C. performed pharmacokinetic and compound metabolism studies; A.E.O. and Y.D. assisted with compound concentration response studies; J.R.M. synthesized SW209049; A.L. and H.M. performed protein mass spectrometry; B.A.P. developed and used the S-Score analysis to identify potential selective toxins and performed unsupervised hierarchical clustering; N.S.W. designed, performed and supervised xenograft, pharmocokinetic, compound metabolism and compound toxicity studies; J.M.R. designed and supervised chemical synthetic strategies, target identification and compound toxicity studies; D.N. designed and supervised target identification, compound selectivity and compound toxicity studies, and wrote the manuscript.

Corresponding authors

Correspondence to Joseph M Ready or Deepak Nijhawan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–5, Supplementary Figures 1–6 and Supplementary Note (Synthetic Procedures) (PDF 19570 kb)

Supplementary Data Set 1

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)

Supplementary Data Set 2

520 small molecules with chemical structure with accompanying toxicity data in 12 NSCLC cell lines and HBEC30KT along with S scores. (XLSX 3190 kb)

Supplementary Data Set 3

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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