First-in-Class Small Molecule to Inhibit CYP11A1 and Steroid Hormone Biosynthesis
Binding of steroid hormones for their cognate receptors regulates the development on most prostate and breast cancers. We hypothesized that CYP11A inhibition might halt the synthesis of steroid hormones, because CYP11A may be the only enzyme that catalyses the initial step of steroid hormone biosynthesis. We speculated that the CYP11A inhibitor might be administered securely so long as the steroids required for existence are replaced. Virtual screening and systematic structure-activity relationship optimization were utilised to build up ODM-208, the very first-in-class, selective, nonsteroidal, dental CYP11A1 inhibitor. Safety of ODM-208 was assessed in rats and Beagle dogs, and effectiveness inside a VCaP castration-resistant cancer of the prostate (CRPC) xenograft mouse model, in rodents and dogs, as well as in six patients with metastatic CRPC. Bloodstream steroid hormone concentrations were measured using liquid chromatography-mass spectrometry. ODM-208 binds to CYP11A1 and inhibited its enzymatic activity. ODM-208 administration brought to rapid, complete, durable, and reversible inhibition from the steroid hormone biosynthesis within an adrenocortical carcinoma cell model in vitro, in adult noncastrated male rodents and dogs, as well as in patients with CRPC. All measured serum steroid hormone concentrations arrived at undetectable levels inside a couple of days from the beginning of ODM-208 administration. ODM-208 was well tolerated with steroid hormone substitute. The toxicity findings were considered associated with CYP11A1 inhibition and were reversed after stopping from the compound administration. Steroid hormone biosynthesis could be effectively inhibited having a small-molecule inhibitor of CYP11A1. The findings claim that administration of ODM-208 is achievable ODM208 with concomitant corticosteroid substitute therapy.