MP34-04 A NEW GENERATION OF N-TERMINAL DOMAIN ANDROGEN RECEPTOR INHIBITORS IN CASTRATION-RESISTANT PROSTATE CANCER MODELS
Bibliographic record
Abstract
You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) IV (MP34)1 Apr 2019MP34-04 A NEW GENERATION OF N-TERMINAL DOMAIN ANDROGEN RECEPTOR INHIBITORS IN CASTRATION-RESISTANT PROSTATE CANCER MODELS Ronan Le Moigne*, Han-Jie Zhou, Nasrin R. Mawji, C. Adriana Banuelos, Jun Wang, Kunzhong Jian, Peter Virsik, Raymond J. Andersen, and Marianne D. Sadar Ronan Le Moigne*Ronan Le Moigne* More articles by this author , Han-Jie ZhouHan-Jie Zhou More articles by this author , Nasrin R. MawjiNasrin R. Mawji More articles by this author , C. Adriana BanuelosC. Adriana Banuelos More articles by this author , Jun WangJun Wang More articles by this author , Kunzhong JianKunzhong Jian More articles by this author , Peter VirsikPeter Virsik More articles by this author , Raymond J. AndersenRaymond J. Andersen More articles by this author , and Marianne D. SadarMarianne D. Sadar More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000555947.83770.aaAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: The androgen receptor (AR) pathway continues to drive castration-resistant prostate cancer (CRPC) even in late stages of the disease. While the latest generation anti-androgens provide clinical benefits to CRPC patients, resistance linked with the ligand binding domain (LBD) inevitably emerges. Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit AR transcription even in the presence of anti-androgen resistance. A Phase I clinical trial of the first generation AR NTD inhibitor, EPI-506 (EPI-002 pro-drug), demonstrated PSA declines in anti-androgen resistant metastatic CRPC patients. However, these declines were minor and of short duration, revealing the need for more potent and metabolically stable NTD inhibitors. Next generation NTD inhibitors (anitens) have been developed and their characterization will be presented. METHODS: Chemical structure activity relationships were developed in order to increase molecule potency in cellular and in vivo assays, while metabolic stability improvements were assessed in in vitro ADME assays and in animal pharmacokinetic studies. In addition, the on-target activity and selectivity was also optimized using a variety of cellular experiments. RESULTS: Next generation anitens, EPI-7170, EPI-7245 and EPI-7324, demonstrated a 10-70 fold improvement on AR-driven cellular potency when compared to the clinical compound EPI-002. While IC50s ranged from <500 nM and ∼1 uM, for EPI-7245 and EPI-7170 respectively, EPI-7324 diplayed potency <300 nM, similar to enzalutamide and bicalutamide. In vitro proliferation assays demonstrated on-target activity for these next-generation anitens, with an IC50 >5 fold higher in AR-independent PC-3 cells compared to AR-dependant LNCaP cells while also displaying activity in AR-V7-driven cellular models. While EPI-7170 exhibited ∼ 70% tumor growth inhibition in castrated mice bearing LNCaP tumors, its ADME and PK profile were not optimal. More recent molecules, including EPI-7245 and EPI-7324, represent next generation aniten molecules with improved potency, selectivity, and metabolic stability compared to EPI-002 and EPI-7170. CONCLUSIONS: The next generation aniten compounds are 10-70 times more active than EPI-002 in cellular potency assays, predicted to be metabolically stable, and selectively inhibit AR transcription in anti-androgen resistant models. Their potential in overcoming anti-androgen clinical resistance to the current generation of anti-androgens will be discussed. Source of Funding: The work was funded by ESSA pharma Houston, TX; Vancouver, Canada; Houston, TX; Vancouver, Canada© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e496-e497 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ronan Le Moigne* More articles by this author Han-Jie Zhou More articles by this author Nasrin R. Mawji More articles by this author C. Adriana Banuelos More articles by this author Jun Wang More articles by this author Kunzhong Jian More articles by this author Peter Virsik More articles by this author Raymond J. Andersen More articles by this author Marianne D. Sadar More articles by this author Expand All Advertisement PDF downloadLoading ...
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.037 | 0.011 |
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".