Tumor-Activated Benzothiazole Inhibitors of Stearoyl-CoA Desaturase

A series
of N-acyl benzothiazoles shows selective
and potent cytotoxicity against cancer cell lines expressing cytochrome
P450 4F11. A prodrug 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 promise that a tumor-activated
prodrug strategy might exploit the essentiality of SCD for tumor growth,
while avoiding toxicity associated with systemic SCD inhibition.