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Discovery and development of ODM-204: A Novel nonsteroidal compound for the treatment of castration-resistant prostate cancer by blocking the androgen receptor and inhibiting CYP17A1

Gerd Wohlfahrt; Mika VJ. Mustonen; Hanna-Maija Metsänkylä; Reetta Riikonen; Päivi Taavitsainen; Riikka Oksala; Petteri Rummakko; Chira Malmström; Mikko Passiniemi; Anu Moilanen; Pekka J. Kallio; Arja Karjalainen; Riikka Huhtaniemi; Meri Ramela

Discovery and development of ODM-204: A Novel nonsteroidal compound for the treatment of castration-resistant prostate cancer by blocking the androgen receptor and inhibiting CYP17A1

Gerd Wohlfahrt
Mika VJ. Mustonen
Hanna-Maija Metsänkylä
Reetta Riikonen
Päivi Taavitsainen
Riikka Oksala
Petteri Rummakko
Chira Malmström
Mikko Passiniemi
Anu Moilanen
Pekka J. Kallio
Arja Karjalainen
Riikka Huhtaniemi
Meri Ramela
Katso/Avaa
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Elsevier Ltd
doi:10.1016/j.jsbmb.2018.02.004
URI
https://doi.org/10.1016/j.jsbmb.2018.02.004
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042719078
Tiivistelmä

We report the discovery of a novel nonsteroidal dual-action compound, ODM-204, that holds promise for treating patients with castration-resistant prostate cancer (CRPC), an advanced form of prostate cancer characterised by high androgen receptor (AR) expression and persistent activation of the AR signaling axis by residual tissue androgens. For ODM-204, has a dual mechanism of action. The compound is anticipated to efficiently dampen androgenic stimuli in the body by inhibiting CYP17A1, the prerequisite enzyme for the formation of dihydrotestosterone (DHT) and testosterone (T), and by blocking AR with high affinity and specificity. In our study, ODM-204 inhibited the proliferation of androgen-dependent VCaP and LNCaP cells in vitro and reduced significantly tumour growth in a murine VCaP xenograft model in vivo. Intriguingly, after a single oral dose of 10-30 mg/kg, ODM-204 dose-dependently inhibited adrenal and testicular steroid production in sexually mature male cynomolgus monkeys. Similar results were obtained in human chorionic gonadotropin-treated male rats. In rats, leuprolide acetate-mediated (LHRH agonist) suppression of the circulating testosterone levels and decrease in weights of androgen-sensitive organs was significantly and dose-dependently potentiated by the co-administration of ODM-204. ODM-204 was well tolerated in both rodents and primates. Based on our data, ODM-204 could provide an effective therapeutic option for men with CRPC.

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