First-in-Class Small Molecule to Inhibit CYP11A1 and Steroid Hormone Biosynthesis

Binding of steroid hormones to their cognate receptors regulates etry. ODM-208 binds to CYP11A1 and inhibited its enzymatic the growth of most prostate and breast cancers. We hypothesized activity. ODM-208 administration led to rapid, complete, durable, that CYP11A inhibition might halt the synthesis of all steroid and reversible inhibition of the steroid hormone biosynthesis in an hormones, because CYP11A is the only enzyme that catalyses the adrenocortical carcinoma cell model in vitro, in adult noncastrated first step of steroid hormone biosynthesis. We speculated that a male mice and dogs, and in patients with CRPC. All measured CYP11A inhibitor could be administered safely provided that the serum steroid hormone concentrations reached undetectable levels steroids essential for life are replaced. Virtual screening and sys- within a few weeks from the start of ODM-208 administration. tematic structure–activity relationship optimization were used to ODM-208 was well tolerated with steroid hormone replacement. develop ODM-208, the first-in-class, selective, nonsteroidal, oral The toxicity findings were considered related to CYP11A1 inhibiCYP11A1 inhibitor. Safety of ODM-208 was assessed in rats and tion and were reversed after stopping of the compound adminisBeagle dogs, and efficacy in a VCaP castration-resistant prostate tration. Steroid hormone biosynthesis can be effectively inhibited cancer (CRPC) xenograft mouse model, in mice and dogs, and in six with a small-molecule inhibitor of CYP11A1. The findings suggest patients with metastatic CRPC. Blood steroid hormone concentra- that administration of ODM-208 is feasible with concomitant tions were measured using liquid chromatography-mass spectrom- corticosteroid replacement therapy.