Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase

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 to the same four of 12 human lung cancer cell lines at low nanomolar concentrations. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible stearoyl CoA desaturase (SCD) inhibitors. 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 were unable to 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.

The Stearoyl-CoA Desaturase-1 (Desat1) in Drosophila cooperated with Myc to Induce Autophagy and Growth, a Potential New Link to Tumor Survival

“…Following our observation that links c-Myc with SCD-1 as a potential survival mechanism, we could speculate that targeting stearoyl CoA desaturase 1 as a novel therapeutic target is of particular relevance given the possibility of using SCD-1 inhibitors [50] in combination with Myc therapies to reduce tumor growth.…”

Structure and Function of Δ9-Fatty Acid Desaturase

“…45) Furthermore, inhibition of SCD1 causes the suppression of proliferation and survival signaling in cancer cells. 46,47) However, because SCD1 is required for a wide range of physiological functions, including lipogenesis in liver and skin, it should be noted that SCD1 inhibitors may have harmful side effects. Recently, tumor-specific irreversible inhibitors of SCD1 were discovered.…”

“…Recently, tumor-specific irreversible inhibitors of SCD1 were discovered. 48) Sensitive cell lines against these compounds express CYP4F11 and metabolize these compounds into irreversible inhibitors of SCD1. 48) Because these compounds are not activated in sebocytes, which do not express CYP4F11, toxicity in the skin can be avoided.…”

“…48) Sensitive cell lines against these compounds express CYP4F11 and metabolize these compounds into irreversible inhibitors of SCD1. 48) Because these compounds are not activated in sebocytes, which do not express CYP4F11, toxicity in the skin can be avoided. 48) Although specific interaction between SCD1 and these inhibitors is reported, the binding site and mechanism for SCD1 inhibition have not been elucidated.…”

“…48) Because these compounds are not activated in sebocytes, which do not express CYP4F11, toxicity in the skin can be avoided. 48) Although specific interaction between SCD1 and these inhibitors is reported, the binding site and mechanism for SCD1 inhibition have not been elucidated. Structure-based evaluation and development of SCD1 inhibitors will be facilitated by reported crystal structures of SCD1, as well as further studies of Δ9-desaturases using biophysical, biochemical, and biological approaches.…”