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

Abstract

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.

Antiproliferative, proapoptotic, and tumor‐suppressing effects of the novel anticancer agent alsevirone in prostate cancer cells and xenografts

“…Similar apoptotic pathways are described in reference [27], where cardiotonic steroid ouabain increased the activities of caspase-3, decreased the total cell viability, and reduced Alsevirone, like other CYP17A1 steroid inhibitors abiraterone, [4] galeterone, [28] and nonsteroid ODM-204, [29] significantly reduced testosterone in BDF1 mice. [30] The concentration of testosterone in blood serum after the administration of alsevirone decreased below the castration level of 0.5 ng/ml [31] and reached about 20.6% of the initial level. The significant reduction in the testosterone blood level is consistent with our findings of CYP17A1 inhibition.…”

Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer

“…The androgen receptor (AR) and its downstream signaling play a critical role in the development and progression of both localized and metastatic prostate cancer . Previous strategies that successfully target AR signaling have focused on blocking androgen synthesis by drugs such as abiraterone and inhibition of AR function by AR antagonists such as enzalutamide and apalutamide (ARN-509). − However, such agents become ineffective in advanced prostate cancer with AR gene amplification, mutation, and alternate splicing. , It is very clear, however, that in most patients with CRPC, the AR protein continues to be expressed and tumors are still dependent on AR signaling. Consequently, AR is an attractive therapeutic target for mCRPC. , …”

Endoplasmic reticulum stress, autophagic and apoptotic cell death, and immune activation by a natural triterpenoid in human prostate cancer cells

“…Specifically, the conversion of androgen precursors to testosterone and dihydrotestosterone (DHT) is an important process in prostate cancer. 20,21 The enzyme 5-α-reductase reduces testosterone to its more active form, DHT, which displays higher binding affinity and increased ligand-receptor binding time with the AR than testosterone. 22 This enzyme has been the target of several anticancer drugs, most notably the steroidal inhibitor finasteride.…”

“…Androgens act on the androgen receptor (AR) in the process of regulation and maintenance of the prostate and also plays a role in prostate cancer development. Specifically, the conversion of androgen precursors to testosterone and dihydrotestosterone (DHT) is an important process in prostate cancer . The enzyme 5‐α‐reductase reduces testosterone to its more active form, DHT, which displays higher binding affinity and increased ligand‐receptor binding time with the AR than testosterone .…”