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Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.

Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ - Sci Rep (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: Orion Corporation, Orion Pharma, Finland.

ABSTRACT
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.


Related in: MedlinePlus

The activation (A) or inhibition (B) of mutant AR(F876L), AR(W741L), and AR(T877A)by ODM-201, ORM-15341, enzalutamide, ARN-509, or bicalutamide and hydroxy (OH)-flutamide (only in the activation assay) was studied in human U2-OS osteosarcoma cells transiently transfected with expression vectors encoding the corresponding mutant AR and an androgen-responsive luciferase reporter gene construct. For assays, steroid-depleted medium was used and luciferase activity was measured after 24 hours. All data points are means of triplicates +SEM. A. Bars represent relative transcriptional activity as percentage of control (testosterone or DHT set as 100%). B. Test compounds were added together with 0.6 nM testosterone (F876L and T877A) or 10 nM DHT (W741L). IC50 values are presented in Table 1.
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f2: The activation (A) or inhibition (B) of mutant AR(F876L), AR(W741L), and AR(T877A)by ODM-201, ORM-15341, enzalutamide, ARN-509, or bicalutamide and hydroxy (OH)-flutamide (only in the activation assay) was studied in human U2-OS osteosarcoma cells transiently transfected with expression vectors encoding the corresponding mutant AR and an androgen-responsive luciferase reporter gene construct. For assays, steroid-depleted medium was used and luciferase activity was measured after 24 hours. All data points are means of triplicates +SEM. A. Bars represent relative transcriptional activity as percentage of control (testosterone or DHT set as 100%). B. Test compounds were added together with 0.6 nM testosterone (F876L and T877A) or 10 nM DHT (W741L). IC50 values are presented in Table 1.

Mentions: Emergence of mutations in AR has been suggested to drive resistance to antiandrogen therapies. The effects of antiandrogens on mutant AR(F876L), AR(W741L), and AR(T877A) were studied in transactivation assays in human U2-OS osteosarcoma cells transiently transfected with expression vectors encoding the corresponding mutant AR and an androgen-responsive luciferase reporter gene construct. The F876L substitution in AR switched enzalutamide and ARN-509 from antagonists to agonists, whereas bicalutamide was agonistic for AR(W741L) mutation (Fig. 2A, Supplementary Fig. S1), as previously reported2223242629. Of the tested antiandrogens, only ODM-201 and its main metabolite ORM-15341 functioned as full antagonists for all tested mutant ARs (Fig. 2B). Data on antagonism of the tested antiandrogens with wtAR and mutated ARs are summarized in Table 1.


Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.

Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ - Sci Rep (2015)

The activation (A) or inhibition (B) of mutant AR(F876L), AR(W741L), and AR(T877A)by ODM-201, ORM-15341, enzalutamide, ARN-509, or bicalutamide and hydroxy (OH)-flutamide (only in the activation assay) was studied in human U2-OS osteosarcoma cells transiently transfected with expression vectors encoding the corresponding mutant AR and an androgen-responsive luciferase reporter gene construct. For assays, steroid-depleted medium was used and luciferase activity was measured after 24 hours. All data points are means of triplicates +SEM. A. Bars represent relative transcriptional activity as percentage of control (testosterone or DHT set as 100%). B. Test compounds were added together with 0.6 nM testosterone (F876L and T877A) or 10 nM DHT (W741L). IC50 values are presented in Table 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490394&req=5

f2: The activation (A) or inhibition (B) of mutant AR(F876L), AR(W741L), and AR(T877A)by ODM-201, ORM-15341, enzalutamide, ARN-509, or bicalutamide and hydroxy (OH)-flutamide (only in the activation assay) was studied in human U2-OS osteosarcoma cells transiently transfected with expression vectors encoding the corresponding mutant AR and an androgen-responsive luciferase reporter gene construct. For assays, steroid-depleted medium was used and luciferase activity was measured after 24 hours. All data points are means of triplicates +SEM. A. Bars represent relative transcriptional activity as percentage of control (testosterone or DHT set as 100%). B. Test compounds were added together with 0.6 nM testosterone (F876L and T877A) or 10 nM DHT (W741L). IC50 values are presented in Table 1.
Mentions: Emergence of mutations in AR has been suggested to drive resistance to antiandrogen therapies. The effects of antiandrogens on mutant AR(F876L), AR(W741L), and AR(T877A) were studied in transactivation assays in human U2-OS osteosarcoma cells transiently transfected with expression vectors encoding the corresponding mutant AR and an androgen-responsive luciferase reporter gene construct. The F876L substitution in AR switched enzalutamide and ARN-509 from antagonists to agonists, whereas bicalutamide was agonistic for AR(W741L) mutation (Fig. 2A, Supplementary Fig. S1), as previously reported2223242629. Of the tested antiandrogens, only ODM-201 and its main metabolite ORM-15341 functioned as full antagonists for all tested mutant ARs (Fig. 2B). Data on antagonism of the tested antiandrogens with wtAR and mutated ARs are summarized in Table 1.

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.

View Article: PubMed Central - PubMed

Affiliation: Orion Corporation, Orion Pharma, Finland.

ABSTRACT
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.


Related in: MedlinePlus