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.
Subject(s)
Antineoplastic Agents/pharmacology , Benzothiazoles/pharmacology , Drug Discovery/methods , Lung Neoplasms/enzymology , Oxamic Acid/analogs & derivatives , Stearoyl-CoA Desaturase/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Benzothiazoles/pharmacokinetics , Benzothiazoles/therapeutic use , Benzothiazoles/toxicity , Cell Line, Tumor , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P450 Family 4 , Female , Humans , Lung Neoplasms/pathology , Male , Mice , Mice, SCID , Molecular Structure , Molecular Targeted Therapy , Oxamic Acid/pharmacokinetics , Oxamic Acid/pharmacology , Oxamic Acid/therapeutic use , Oxamic Acid/toxicity , Protein Binding , Sebaceous Glands/drug effects , Sebaceous Glands/enzymology , Sebaceous Glands/pathology , Xenograft Model Antitumor AssaysABSTRACT
Porcupine is a member of the membrane-bound O-acyltransferase family of proteins. It catalyzes the palmitoylation of Wnt proteins, a process required for their secretion and activity. We recently disclosed a class of small molecules (IWPs) as the first reported Porcn inhibitors. We now describe the structure-activity relationship studies and the identification of subnanomolar inhibitors. We also report herein the effects of IWPs on Wnt-dependent developmental processes, including zebrafish posterior axis formation and kidney tubule formation.
