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

Autor: Passiniemi Mikko, Gerd Wohlfahrt, Petteri Rummakko, Reetta Riikonen, Riikka Huhtaniemi, Pekka Kallio, Päivi Taavitsainen, Karjalainen Arja, Chira Malmström, Hanna-Maija Metsänkylä, Meri Ramela, Riikka Oksala, Anu Moilanen, Mika Mustonen
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
Clinical Biochemistry
Mice
Nude
Apoptosis
Pharmacology
urologic and male genital diseases
Biochemistry
Steroid
Rats
Sprague-Dawley
Mice
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Endocrinology
In vivo
Drug Discovery
LNCaP
Androgen Receptor Antagonists
Tumor Cells
Cultured
Animals
Humans
Medicine
Enzyme Inhibitors
Molecular Biology
Testosterone
Cell Proliferation
business.industry
Imidazoles
Steroid 17-alpha-Hydroxylase
Haplorhini
Cell Biology
medicine.disease
Xenograft Model Antitumor Assays
Rats
Androgen receptor
Prostatic Neoplasms
Castration-Resistant
030104 developmental biology
Receptors
Androgen
CYP17A1
030220 oncology & carcinogenesis
Dihydrotestosterone
Molecular Medicine
business
medicine.drug
Zdroj: The Journal of Steroid Biochemistry and Molecular Biology. 192:105115
ISSN: 0960-0760
Popis: 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.
Databáze: OpenAIRE
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