Description
ODM-201 is an androgen receptor (AR) antagonist (K
i = 11 nM). It inhibits AR transactivation in U2OS osteosarcoma cells expressing human wild-type and mutant ARs (IC
50s = 65, 66, 1,500, and 1,782 nM for wild-type, AR
F876L, AR
W741L, and AR
T877A, respectively). ODM-201 prevents androgen-induced AR nuclear translocation in AR-overexpressing HS-HEK293 and LNCaP cells and suppresses androgen-induced proliferation of VCaP cells (IC
50 = 230 nM).
In vivo, ODM-201 (50 mg/kg per day) reduces tumor growth in a VCaP castrated mouse xenograft model. It also inhibits tumor growth without increasing serum testosterone levels in a VCaP intact mouse xenograft model.
Description
ODM-201 is a novel androgen receptor (AR) inhibit designed to inhibit the growth of prostate cancer cells through binding to the AR to inhibit the testosterone-induced AR nuclear translocation. It is particularly used in patients with progressive metastatic castration-resistant prostate cancer. It is effective in inhibiting the activity of some mutant ARs emerging during antiandrogen therapies, including the F876L mutation version which is resistant to enzalutamide and ARN-509 (the second-generation antiandrogens).Therefore, it has potential to overcome the resistance issue occurring upon AR-targeted therapies.
References
Moilanen, Anu Maarit, et al. "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies." Sci Rep 5.2(2015):12007.
Fizazi, Karim, et al. "ODM-201, a new generation androgen receptor inhibitor for castration-resistant prostate cancer: Preclinical and phase I data." Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of 2013.
Fizazi, K, et al. "Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial." Lancet Oncology 5.9(2014):975-85.
