Identification of a first enzymatic activator of a 17β-hydroxysteroid dehydrogenase

Small molecule activators that directly modulate the activity of an enzyme are uncommon entities, and such activators had never yet been identified for any 17β-hydroxysteroid dehydrogenase (17β-HSD). We hereby report the fortuitous discovery of a steroid derivative that caused an up to 3-fold increase in the activity of 17β-HSD12. The stimulation of estrone to estradiol conversion has been characterized in intact and homogenized stably transfected HEK-293 cells and has also been observed in T47D breast cancer cells. Structure-activity relationships closely linked to the nature of the substituent on the [1,3]oxazinan-2-one ring of an estradiol derivative emerged from this study and may help in the identification of a previously unsuspected endogenous activation of 17β-HSD12. This activator will therefore be a useful tool to study this relatively unknown enzyme as well as the possible activation of other 17β-HSD family members.