Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase

Structure of cytochrome P450

Structure of cytochrome P450. Image by B.Kleine, licensed under CC BY-SA 3.0.

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

Nature Chemical Biology

February 01, 2016

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. (Publication Abstract)

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Last updated: October 30, 2018