Abstract B14: Developing small-molecule inhibitors to the androgen receptor N-terminus domain for the treatment of advanced prostate cancer
Bibliographic record
Abstract
Abstract Androgen ablation therapy remains the gold standard for the treatment of advanced prostate cancer, but unfortunately, it is not curative and eventually the disease will return as lethal castration-resistant prostate cancer (CRPC). There is evidence supporting the concept that development of CRPC is causally related to continued transactivation of androgen receptor (AR). Suspected mechanisms for continued AR activity in spite of castrate levels of androgen include: amplification or overexpression of AR; gain-of-function mutations allowing AR to be activated by steroids or antiandrogens; ligand-independent activation by growth factors, cytokines, or kinases; overexpression of AR coactivators; intracrine signaling by increased intratumoral androgens; and/or expression of constitutively active splice variants of AR that lack the C-terminal ligandbinding domain (LBD). All current therapies that target the AR are dependent on the presence of its C-terminal LBD. However, it is the N-terminal domain (NTD) of the AR that is the “Achilles Heel” of AR activity, with activation function-1 (AF-1) being essential for AR activity regardless of androgen. Our efforts have been focused upon developing drugs to the AR NTD and have yielded EPI-001 a small molecule, sintokamide peptides, and decoys to the AR NTD. Of these, EPI-001 is the best characterized as previously shown to inhibit essential protein-protein interactions that are required for AR transcriptional activity. EPI-001 and its analogues (generally referred to as “EPI”) have great promise for clinical development based upon its unique mechanism of action, specificity, low toxicity, and cytoreductive antitumor activity. EPI blocked transcriptional activity of full-length and AR variants as well as specifically inhibited AR-dependent cell proliferation. EPI directly and specifically interacted with AF1 and did not interact with denatured AF1 as shown using in vitro binding assays. Specific and direct interaction of EPI with the endogenous AR occurred in living cells as shown using click chemistry. EPI-001 had 86% oral bioavailability, a half-life of 3.4 hours, and plasma levels at the effective concentration of 10 ug/ml were achieved with oral dosing. Consistent with excellent oral bioavailability, oral dosing of EPI inhibited VCaP tumor growth in castrated animals. VCaP human prostate cancer cells express an abundance of full-length AR as well as constitutively active AR splice variant lacking LBD. Evidence for EPI targeting the AR transcriptional program in vivo, was provided by reduced transcripts of UBE2C, CDC20, cyclinA2, and AKT1 in harvested VCaP xenografts from animals treated orally with EPI. In conclusion, EPI is an antagonist of AR NTD that blocks the activity of AR, including constitutively active AR splice variants, by a mechanism that involves direct interaction with the NTD. Oral dosing of EPI has antitumor activity in prostate cancer xenografts that express AR variant. Together these data support the clinical development of EPI for the treatment of CRPC. Funding: NIH (2R01 CA105304) and US Army Medical Research and Materiel Command Prostate Cancer Research Program (PC100761). Note: This abstract was not presented at the conference because the presenter was unable to attend. Citation Format: Marianne D. Sadar, Jae-Kyung Myung, Iain McEwan, Stephen Plymate, Raymond J. Andersen, Carmen A. Banuelos, Nasrin R. Mawji, Jun Wang, Javier Garcia Fernandez, Amy Tien, Iran Tavakoli, Yu Chi Yang, Simon Haile. Developing small-molecule inhibitors to the androgen receptor N-terminus domain for the treatment of advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B14.
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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) | 0.003 | 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".