Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.
Bottom Line: Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR.In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice.In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs.
Affiliation: Orion Corporation, Orion Pharma, Finland.
Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC.
No MeSH data available.
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Mentions: To investigate the effect of antiandrogens on the subcellular localization of AR, immunocytochemical labeling with an anti-AR antibody in AR overexpressing HS-HEK293 cells was used. As shown in Fig. 3A, AR was predominantly cytoplasmic in the absence of androgen, and exposure to testosterone markedly increased the nuclear-cytoplasmic ratio of AR immunofluorescence intensity, indicating the movement of AR from the cytoplasm to the nucleus. In the presence of bicalutamide, AR was largely nuclear, indicating that bicalutamide failed to block the testosterone-induced nuclear translocation of AR. In contrast, in the presence of ODM-201, ORM-15341, enzalutamide, or ARN-509, AR was predominantly cytoplasmic, showing that these antiandrogens inhibit the androgen-induced nuclear translocation of overexpressed AR to same extent (Fig. 3A,B). Corresponding results were obtained also with an AR-overexpressing PC cell line (LNCaP) (Supplementary Fig. S2).
No MeSH data available.