The TRPA1 channel in the skin contributes to sustained as well noxious mechanical stimulus-evoked postoperative pain, whereas the spinal TRPA1 channel contributes predominantly to innocuous mechanical stimulus-evoked postoperative pain.

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

340 Background: Castration-resistant prostate cancer (CRPC) is a major cause of cancer mortality worldwide. The mechanisms behind the development of resistance are complex and not fully understood; altered androgen synthesis, androgen receptor (AR) overexpression or gene amplification, and mutations have been indentified. However, tumor growth may still be responsive to therapies that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1. ODM-208 is an oral, non-steroidal and selective inhibitor of CYP11A1 enzyme that suppresses the synthesis of all steroid hormones and their precursors. Methods: The inhibition of CYP11A1 was measured in vitro by the formation of radiolabelled isocapronic acid in a human adrenal cortex cell line (H295R), and further analysing pregnenolone (Preg) and testosterone (T) formation by ELISA. The tumor growth inhibition of ODM-208 alone or in combination with prednisone (Pred) was studied in VCaP CRPC xenograft where also concentrations of main steroid hormones progesterone (P), corticosterone (CORT) and T in tumors and adrenals were analysed. In addition, plasma ACTH and LH levels were measured at the end of the xenograft study. In dogs an ACTH stimulation test was done. Toxicity studies were conducted in rats and dogs. Results: ODM-208 potently inhibits CYP11A1 and synthesis of Preg and T with nM concentrations in vitro. In the VCaP CRPC xenograft ODM-208 alone and in combination with Pred significantly inhibited tumor growth. Concentrations of T, P and CORT were significantly decreased in the adrenals, indicating strong CYP11A1 inhibition. Also, significantly decreased steroid levels in tumors was observedhe Pred combination increased plasma ACTH levels less than ODM-208 alone, whereas no difference was seen in the LH. In dogs ACTH-stimulated cortisol production was significantly inhibited after single oral dose of ODM-208. In toxicological studies ODM-208 showed expected reversible findings in target tissues, mainly related to the pharmacology. Conclusions: ODM-208 shows promising antitumor activity in preclinical CRPC models with favorable toxicological profile. Thus, ODM-208 might have potential for treating the patients with CRPC.

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