- |||||||||| ralaniten acetate (EPI-506) / ESSA Pharma
Journal: Drugging the Undruggable: Targeting the N-Terminal Domain of Nuclear Hormone Receptors. (Pubmed Central) - Sep 20, 2022 This chapter will provide an introduction of the structure and function of the domains of nuclear hormone receptors, followed by a discussion of the rationale supporting the development of N-terminal domain inhibitors. Chemistry and mechanisms of action of small molecule inhibitors will be described with emphasis on N-terminal domain inhibitors developed to the androgen receptor including those in clinical trials.
- |||||||||| ralaniten acetate (EPI-506) / ESSA Pharma, EPI-7386 / ESSA Pharma
Molecular characterization of next generation AR-NTD inhibitors (Exhibition Hall) - Sep 3, 2022 - Abstract #AACRNCIEORTC2022AACR_NCI_EORTC_340; P1, P1/2 This work highlights the potential for combination therapies which utilize both classes of inhibitors. An ongoing clinical trial is currently investigating EPI-7386 in combination with enzalutamide (NCT05075577).
- |||||||||| Xtandi (enzalutamide) / Pfizer, Astellas, Bausch Health, EPI-7170 / ESSA Pharma
Journal, Combination therapy: Combination therapy with androgen receptor N-terminal domain antagonist EPI-7170 and enzalutamide yields synergistic activity in AR-V7-positive prostate cancer. (Pubmed Central) - Sep 12, 2021 Both full-length AR and truncated AR-Vs require a functional N-terminal domain (NTD) for transcriptional activity thereby providing rationale for the development of ralaniten (EPI-002) as a first-in-class antagonist of the AR-NTD...In addition, this drug enhanced the anti-tumor effect of enzalutamide in enzalutamide-resistant CRPC preclinical models. Thus, a combination therapy targeting both the NTD and LBD of AR, and thereby blocking both full-length AR and AR-Vs, has potential for the treatment of enzalutamide-resistant CRPC.
- |||||||||| Xtandi (enzalutamide) / Pfizer, Astellas, Bausch Health, ralaniten acetate (EPI-506) / ESSA Pharma
Journal: Isolation and characterization of castration-resistant prostate cancer LNCaP95 clones. (Pubmed Central) - Jul 3, 2021 In castrated immunodeficient animals, the growth of subcutaneous xenografts of the D3 clone was the most reproducible compared to the parental cell line and other clones. These data support that the enzalutamide-resistant LNCaP95-D3 subline may be suitable as a xenograft tumor model for preclinical drug development with improved reproducibility.
- |||||||||| ralaniten acetate (EPI-506) / ESSA Pharma
Journal: Discovery of drugs that directly target the intrinsically disordered region of the androgen receptor. (Pubmed Central) - Mar 17, 2021 The discovery of small molecules, including the libraries used, proven binders to the AR-NTD, and site of interaction of these small molecules in the AR-NTD are presented along with discussion of the Phase I clinical trial.Expert opinion: The lack of drugs in the clinic that directly bind IDPs/IDRs reflects the difficulty of targeting these proteins and obtaining specificity. However, it may also point to an inappropriateness of too closely borrowing concepts and resources from drug discovery to folded proteins.
- |||||||||| ralaniten acetate (EPI-506) / ESSA Pharma
Journal: Revealing Metabolic Liabilities of Ralaniten To Enhance Novel Androgen Receptor Targeted Therapies. (Pubmed Central) - Apr 9, 2020 P1/2 Therefore, we tested an analogue of ralaniten (EPI-045) which was resistant to glucuronidation and demonstrated superiority to ralaniten in our resistant model. These data support that analogues of ralaniten designed to mitigate glucuronidation may optimize clinical responses to AR-NTD inhibitors.
- |||||||||| EPI-7386 / ESSA Pharma
Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor (Board 117: Level 2 - Hall D) - Sep 18, 2019 - Abstract #AACRNCIEORTC2019AACR_NCI_EORTC_344; Importantly, the combination of enzalutamide with EPI-7386 demonstrated a more robust and consistent PSA and antitumor response in the VCaP model...Conclusion The next generation aniten compound EPI-7386 is more active and metabolically stable than EPI-506...As a single agent, EPI-7386 may overcome anti-androgen clinical resistance in advanced mCRPC as well as potentially in combination therapy with anti-androgens in earlier stages of the disease. The clinical strategy supporting the development of this Aniten N-terminal domain inhibitor of AR will be discussed.
- |||||||||| ralaniten acetate (EPI-506) / ESSA Pharma
Enrollment change, Trial completion date, Trial termination, Trial primary completion date, Metastases: Safety and Anti-Tumor Study of Oral EPI-506 for Patients With Metastatic Castration-Resistant Prostate Cancer (clinicaltrials.gov) - Mar 1, 2018 P1/2, N=28, Terminated, The clinical strategy supporting the development of this new generation of Aniten will be discussed. N=166 --> 28 | Active, not recruiting --> Terminated | Trial primary completion date: Mar 2018 --> Dec 2017 | Trial completion date: Dec 2018 --> Dec 2017; At end of Phase 1 excessive high pill burden (18 capsules/day)
- |||||||||| Biomarker, Review, Journal: Androgen Receptor-Dependent and -Independent Mechanisms Involved in Prostate Cancer Therapy Resistance. (Pubmed Central) - Jun 13, 2017
AR-independent resistance mechanisms include glucocorticoid receptor activation, immune-mediated resistance, and neuroendocrine differentiation. The development of novel agents, such as seviteronel, apalutamide, and EPI-001/EPI-506, as well as the identification and validation of novel predictive biomarkers of resistance, may lead to improved therapeutics for mCRPC patients.
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