2. Academic Validation
  3. Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase

Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase

  • Nat Chem Biol. 2016 Apr;12(4):218-25. doi: 10.1038/nchembio.2016.
Panayotis C Theodoropoulos 1,  Stephen S Gonzales 1,  Sarah E Winterton 1,  Carlos Rodriguez-Navas 2,  John S McKnight 3,  Lorraine K Morlock 1,  Jordan M Hanson 1,  Bethany Cross 1,  Amy E Owen 3,  Yingli Duan 3,  Jose R Moreno 1,  Andrew Lemoff 1,  Hamid Mirzaei 1 4,  Bruce A Posner 1 4,  Noelle S Williams 1 4,  Joseph M Ready 1 4,  Deepak Nijhawan 1 3 4
Affiliations

Affiliations

  • 1 Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
  • 2 Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, Texas, USA.
  • 3 Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
  • 4 Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA.
PMID: 26829472 DOI: 10.1038/nchembio.2016
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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