Steroid derivatives as pure antagonists of the androgen receptor
S. Gauthier, C. Martel & F. Labrie
Introduction: While the androgens of testicular origin (representing about 50% of total androgens in men over 50 years) can be completely eliminated by surgical or medical castration with GnRH (gonadotropin-releasing hormone) agonists or antagonists, the antiandrogens currently available as blockers of androgen binding to the androgen receptor (AR), namely bicalutamide (BICA), flutamide (FLU) and nilutamide have too weak affinity to completely neutralize the 50% of androgens made locally from dehydroepiandrosterone (DHEA) in the prostate cancer tissue by the mechanisms of intracrinology.
Description of methods/design: Series of steroid derivatives having pure and potent antagonistic activity on the human and rodent AR were synthetized. Assays of AR binding and activity in carcinoma mouse Shionogi and human LNCaP cells as well as in vivo bioavailability measurements and in vivo prostate weight assays in the rat were used.
Results: The chosen lead steroidal compound, namely EM-5854, has a 3.7-fold higher affinity than BICA for the human AR while EM-5855, an important metabolite of EM-5854, has a 94-fold higher affinity compared to BICA. EM-5854 and EM-5855 are 14 times more potent than BICA in inhibiting androgen (R1881)-stimulated prostatic specific antigen (PSA) secretion in human prostatic carcinoma LNCaP cells in vitro. MDV3100 has a potency comparable to bicalutamide in these assays. Depending upon the oral formulation, EM-5854 is 5- to 10-times more potent than BICA to inhibit dihydrotestosterone (DHT)-stimulated ventral prostatic weight in vivo in the rat. These data indicating the high potency of EM-5854 and EM-5855 are supported by respective 40-fold and 105-fold higher potencies of these two compounds compared to BICA to inhibit cell proliferation in the androgen-sensitive Shionogi carcinoma cell model.
Conclusion: The present data suggest the possibility of a much higher potency of EM-5854 or EM 5855 compared to BICA (Casodex) for the treatment of prostate cancer in men.
Declaration of interest: I fully declare a conflict of interest. Details below:
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.