Figure 15.

Biotransformation of ingenol disoxate to its main human metabolite (M27), using a microbial strain. M27 is a metabolite that was more prevalent in humans than in preclinical species, i.e. a disproportionate metabolite, and thus subject to the FDA’s MIST guidelines. Yield of M27 was optimized by early harvest of the reaction to prevent onward oxidation to dihydroxylated derivatives, resulting in the purification of 100s of milligrams of the metabolite for further evaluation. M27 was shown to have similar pharmacological effects to the parent compound but was less potent.⁶²