Tumor-Activated Benzothiazole Inhibitors of Stearoyl-CoA Desaturase

Abstract

A series of N-acyl benzothiazoles show selective and potent cytotoxicity against cancer cell lines expressing cytochrome P450 4F11. A pro-drug form is metabolized by cancer cells into an active inhibitor of stearoyl-CoA desaturase, SCD. Substantial variation on the acyl portion of the inhibitors allowed the identification of (R)-27, which balanced potency, solubility and lipophilicity to allow proof-of-concept studies in mice. The prodrugs were activated inside the tumor, where they can arrest tumor growth. Together, these observations offer the promise that a tumor-activated prodrug strategy might exploit the essentiality of SCD for tumor growth while avoiding toxicity associated with systemic SCD inhibition.