Steroid derivatives as pure antagonists of the androgen receptor
Bibliographic record
Abstract
Abstract Background 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 other 50% of androgens made locally from dehydroepiandrosterone (DHEA) in the prostate cancer tissue by the mechanisms of intracrinology. Materials and methods Series of steroid derivatives having pure and potent antagonistic activity on the human and rodent AR were synthesized. 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 for the human AR 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 while MDV3100 has lower activity than BICA in this in vivo model. These data are supported by respective 40-fold and 105-fold higher potencies of EM-5854 and EM-5855 compared to BICA to inhibit cell proliferation in the androgen-sensitive Shionogi carcinoma cell model. Conclusions Although the present preclinical results data need evaluation in clinical trials in men, combination of the data obtained in vitro in human LNCaP cells as indicator of potency in the human prostate and the data on metabolism evaluated in vivo on ventral prostate weight in the rat, could suggest the possibility of a 70- to 140-fold higher potency of EM-5854 compared to bicalutamide (Casodex) for the treatment of prostate cancer in men.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".