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

胆固醇侧链裂解酶 类固醇 激素 睾酮(贴片) 甾体生物合成 类固醇激素 内科学 内分泌学 药理学 甾体11β-羟化酶 化学 生物 医学 细胞色素P450 新陈代谢
作者
Mari Karimaa,Reetta Riikonen,Henna Kettunen,Päivi Taavitsainen,Meri Ramela,Marcin Chruściel,Stefan Karlsson,Petteri Rummakko,Outi Simola,Gerd Wohlfahrt,Pasi Hakulinen,Annamari Vuorela,Heikki Joensuu,Tapio Utriainen,Karim Fizazi,Riikka Oksala
出处
期刊:Molecular Cancer Therapeutics [American Association for Cancer Research]
卷期号:21 (12): 1765-1776 被引量:14
标识
DOI:10.1158/1535-7163.mct-22-0115
摘要

Abstract 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, because 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, nonsteroidal, 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 noncastrated 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.
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