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The diterpenoid ester ingenol mebutate (IngMeb) is the active ingredient in the topical drug Picato, a first-in-class treatment for the precancerous skin condition actinic keratosis. IngMeb is proposed to exert its therapeutic effects through a dual mode of action involving (i) induction of cell death that is associated with mitochondrial dysfunction followed by (ii) stimulation of a local inflammatory response, at least partially driven by protein kinase C (PKC) activation. Although this therapeutic model has been well characterized, the complete set of molecular targets responsible for mediating IngMeb activity remains ill-defined. Here, we have synthesized a photoreactive, clickable analogue of IngMeb and used this probe in quantitative proteomic experiments to map several protein targets of IngMeb in human cancer cell lines and primary human keratinocytes. Prominent among these targets was the mitochondrial carnitine-acylcarnitine translocase SLC25A20, which we show is inhibited in cells by IngMeb and the more stable analogue ingenol disoxate (IngDsx), but not by the canonical PKC agonist 12- O -tetradecanoylphorbol-13-acetate (TPA). SLC25A20 blockade by IngMeb and IngDsx leads to a buildup of cellular acylcarnitines and blockade of fatty acid oxidation (FAO), pointing to a possible mechanism for IngMeb-mediated perturbations in mitochondrial function.

Chemical Proteomics Identifies SLC25A20 as a Functional Target of the Ingenol Class of Actinic Keratosis Drugs