Background: The androgen receptor (AR) pathway drives most metastatic castration-resistant prostate cancers (mCRPC) even in late stages of the disease and resistance to ligand binding domain (LBD)-linked therapies inevitably emerges. Mechanisms of resistance to anti-androgens include AR gene amplification, C-terminal ligand-binding domain (LBD) mutations and expression of constitutively-active truncated AR splice variants lacking the LBD (e.g. AR-V7). Inhibition of the N-terminal domain (NTD) of the AR can inhibit transcriptional activity even in the presence of LBD-driven resistance. A Phase I clinical trial of the first-generation AR NTD inhibitor, EPI-506, demonstrated minor PSA declines in anti-androgen refractory mCRPC patients, revealing the need for more potent and metabolically stable NTD inhibitors. EPI-7386 represents a second generation of NTD inhibitors (Anitens) that are more active and more metabolically stable than EPI-506. Methods: Chemical structure activity relationships were explored to increase molecule potency while maintaining target specificity using a wide variety of CRPC models in vivo and in vitro. The stability and selectivity of the molecules were characterized with a panel of selective screening and functional assays. The mechanism of action and pathway engagement markers were followed by qPCR and RNAseq. Results: EPI-7386 was chosen as the IND candidate. The molecule demonstrated a 20-fold improvement in AR-driven cellular potency compared to EPI-002, while being highly stable in human and animal hepatocytes. In vitro proliferation assays demonstrated on-target activity across a panel of prostate cancer cell lines, with activity demonstrated in AR-V7-driven cellular models. The antiproliferative effect correlated with the inhibitory effect on AR driven genes, including specifically AR-V7 driven genes such as UBE2C. EPI-7386 controlled tumor growth and induced tumor regressions in several CRPC xenografts, including AR-V7-driven 22Rv1 and enzalutamide resistant LNCaP95 models, as well as the VCaP model. Importantly, the combination of enzalutamide with EPI-7386 demonstrated a more robust and consistent PSA and antitumor response in the VCaP model. EPI-7386 was well tolerated in animal models, and therapeutic levels could be achieved without displaying signs of toxicity in a 14-day rat study. Pharmacodynamic markers will be presented, in addition to their incorporation in the future clinical plan. Conclusions: The next generation aniten compound EPI-7386 is more active and metabolically stable than EPI-506. It shows on-target activity in AR full length and AR-V7 driven models, and demonstrates a high therapeutic index in preclinical models. 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. Citation Format: Ronan Le Moigne, C. Adriana Banuelos, Nasrin R Mawji, Teresa Tam, Jun Wang, Kunzhong Jian, Raymond J Andersen, Alessandra Cesano, Marianne D Sadar, Han-Jie Zhou, Peter Virsik. Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B117. doi:10.1158/1535-7163.TARG-19-B117

Ronan Le Moigne; C. Adriana Banuelos; Nasrin R Mawji; Teresa Tam; Jun Wang; Kunzhong Jian; Raymond J Andersen; Alessandra Cesano; Marianne D Sadar; Han-Jie Zhou; Peter Virsik. Abstract B117: Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor. Molecular Cancer Therapeutics 2019, 18, B117 -B117.

Ronan Le Moigne, C. Adriana Banuelos, Nasrin R Mawji, Teresa Tam, Jun Wang, Kunzhong Jian, Raymond J Andersen, Alessandra Cesano, Marianne D Sadar, Han-Jie Zhou, Peter Virsik. Abstract B117: Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor. Molecular Cancer Therapeutics. 2019; 18 (12_Supplem):B117-B117.

Ronan Le Moigne; C. Adriana Banuelos; Nasrin R Mawji; Teresa Tam; Jun Wang; Kunzhong Jian; Raymond J Andersen; Alessandra Cesano; Marianne D Sadar; Han-Jie Zhou; Peter Virsik. 2019. "Abstract B117: Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor." Molecular Cancer Therapeutics 18, no. 12_Supplem: B117-B117.

The androgen receptor (AR) is a key driver in the growth of prostate cancer and remains a crucial target for therapeutic intervention even in late stages of the disease. While current anti-androgen therapies targeting directly or indirectly the AR ligand binding domain (LBD) are initially effective, resistance ultimately develops. The selective targeting of the N-terminal domain (NTD) of the AR represents a novel method of blocking AR signaling to by-pass LBD-related resistance. EPI-7386 is a potent and metabolically stable NTD inhibitor (aniten) currently in a phase 1 dose-escalation study in mCRPC patients. Here we report the results of a comprehensive in vitro characterization of its mechanism of action. The potency and selectivity of EPI-7386 was determined in cellular models expressing different forms of AR using reporter and cell viability assays. Target engagement was measured by a Cellular Thermal Shift Assay (CETSA). Both Nanostring and RNAseq were used to explore the activity of EPI-7386 on the AR transcriptome. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR were carried out to determine the effect of EPI-7386 on AR genomic occupancy. EPI-7386 exhibited potent activity in inhibiting full-length AR (AR-FL) driven transcriptional activity and also strongly impaired the transcriptional activity and the viability of cellular models driven exclusively by truncated AR protein. Using CETSA, we confirmed that EPI-7386 induced a thermal shift of both AR-FL and AR-V7 (lacking the AR LBD) in LNCaP and LNCaP95, respectively, which is an indication of AR target engagement by EPI-7386. ChIP analyses allowed a deeper understanding of epigenetic and transcriptional regulation driven by EPI-7386. It showed EPI-7386 inhibits androgen-activated AR binding to target gene loci such as KLK3. Additionally, EPI-7386 suppresses AR-regulated target gene expression in a comparable manner as lutamides in three human prostate cancer cell lines, LNCaP, 22Rv1, and VCaP, with a few notable exceptions. As a consequence, the combination of EPI-7386 with lutamides resulted in broader and deeper inhibition of AR-associated transcriptional activity in both LNCaP and VCaP cells. In AR-V7 driven cell lines, LNCaP95 and 22Rv1, EPI-7386 showed superior activity to enzalutamide in inhibiting AR-regulated genes expression. In conclusion, EPI-7386 is a potent AR NTD inhibitor that has the capacity to by-pass AR LBD resistance mechanisms to current anti-androgen therapies by uniquely inhibiting AR-mediated signaling. The agent has the potential for providing clinical benefit as a single agent in patients whose tumors are progressing on anti-androgens or in combination with current anti-androgens in earlier line patients. The Phase I dose escalation first in human clinical trial of EPI-7386 single agent (NCT04421222) is currently enrolling. Citation Format: Nan Hyung Hong, Shihua Sun, Peter Virsik, Alessandra Cesano, Elahe A. Mostaghel, Stephen R. Plymate, Han-Jie Zhou, Ronan Le Moigne. Comprehensive in vitro characterization of the mechanism of action of EPI-7386, an androgen receptor N-terminal domain inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1209.

Nan Hyung Hong; Shihua Sun; Peter Virsik; Alessandra Cesano; Elahe A. Mostaghel; Stephen R. Plymate; Han-Jie Zhou; Ronan Le Moigne. Abstract 1209: Comprehensive in vitro characterization of the mechanism of action of EPI-7386, an androgen receptor N-terminal domain inhibitor. Cancer Research 2021, 81, 1209 -1209.

Nan Hyung Hong, Shihua Sun, Peter Virsik, Alessandra Cesano, Elahe A. Mostaghel, Stephen R. Plymate, Han-Jie Zhou, Ronan Le Moigne. Abstract 1209: Comprehensive in vitro characterization of the mechanism of action of EPI-7386, an androgen receptor N-terminal domain inhibitor. Cancer Research. 2021; 81 (13_Supplem):1209-1209.

Nan Hyung Hong; Shihua Sun; Peter Virsik; Alessandra Cesano; Elahe A. Mostaghel; Stephen R. Plymate; Han-Jie Zhou; Ronan Le Moigne. 2021. "Abstract 1209: Comprehensive in vitro characterization of the mechanism of action of EPI-7386, an androgen receptor N-terminal domain inhibitor." Cancer Research 81, no. 13_Supplem: 1209-1209.

Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375–86. ©2017 AACR.

Ronan Le Moigne; Blake T. Aftab; Stevan Djakovic; Eugen Dhimolea; Eduardo Valle; Megan Murnane; Emily M. King; Ferdie Soriano; Mary-Kamala Menon; Zhi Yong Wu; Stephen T. Wong; Grace J. Lee; Bing Yao; Arun P. Wiita; Christine Lam; Julie Rice; Jinhai Wang; Marta Chesi; P. Leif Bergsagel; Marianne Kraus; Christoph Driessen; Szerenke Kiss Von Soly; F. Michael Yakes; David Wustrow; Laura Shawver; Han-Jie Zhou; Thomas G. Martin; Jeffrey L. Wolf; Constantine S. Mitsiades; Daniel J. Anderson; Mark Rolfe. The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma. Molecular Cancer Therapeutics 2017, 16, 2375 -2386.

Ronan Le Moigne, Blake T. Aftab, Stevan Djakovic, Eugen Dhimolea, Eduardo Valle, Megan Murnane, Emily M. King, Ferdie Soriano, Mary-Kamala Menon, Zhi Yong Wu, Stephen T. Wong, Grace J. Lee, Bing Yao, Arun P. Wiita, Christine Lam, Julie Rice, Jinhai Wang, Marta Chesi, P. Leif Bergsagel, Marianne Kraus, Christoph Driessen, Szerenke Kiss Von Soly, F. Michael Yakes, David Wustrow, Laura Shawver, Han-Jie Zhou, Thomas G. Martin, Jeffrey L. Wolf, Constantine S. Mitsiades, Daniel J. Anderson, Mark Rolfe. The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma. Molecular Cancer Therapeutics. 2017; 16 (11):2375-2386.

Ronan Le Moigne; Blake T. Aftab; Stevan Djakovic; Eugen Dhimolea; Eduardo Valle; Megan Murnane; Emily M. King; Ferdie Soriano; Mary-Kamala Menon; Zhi Yong Wu; Stephen T. Wong; Grace J. Lee; Bing Yao; Arun P. Wiita; Christine Lam; Julie Rice; Jinhai Wang; Marta Chesi; P. Leif Bergsagel; Marianne Kraus; Christoph Driessen; Szerenke Kiss Von Soly; F. Michael Yakes; David Wustrow; Laura Shawver; Han-Jie Zhou; Thomas G. Martin; Jeffrey L. Wolf; Constantine S. Mitsiades; Daniel J. Anderson; Mark Rolfe. 2017. "The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma." Molecular Cancer Therapeutics 16, no. 11: 2375-2386.

220 Background: EPI-506, pro-drug of EPI-002, was a first-in-class oral small molecule from the Aniten family of compounds, which inhibit androgen receptor (AR) activity by binding to the N-terminal domain of the AR. EPI-506 was tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC) resistant to current therapies and demonstrated a favorable tolerability profile with signs of moderate efficacy. Metabolic vulnerabilities in the chemical scaffold of EPI-506 were identified and new Aniten molecules, EPI-7170 and EPI-7245 , with improved potency, metabolic stability and pharmaceutical properties have been generated. 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 demonstrated a 10-20 fold improvement on AR-driven cellular potency, with IC50’s of 0.5-1 uM when compared to 10-12 uM for EPI-002. In vitro proliferation assays demonstrated on target activity, with an IC50 ~ 2 uM in LNCaP and > 10 uM in the AR-independent cell model PC-3. EPI-7170 was also active in AR-V7-driven LNCaP95 cells. The antiproliferative effect was in alignment with the inhibitory effect on a subset of AR driven genes. In vivo activity in castrated mice bearing LNCaP tumors showed tumor growth inhibition of approximately 70%. While EPI-7170 represents a major advance, subsequent chemistry efforts led to the generation of EPI-7245 and other next generation Anitens which exhibit IC50’s < 500 nM and favorable ADME and PK profiles. Conclusions: Promising next-generation Aniten compounds have been identified. Major chemistry efforts led to the identification of several Anitens with > 10-20 fold improvements in cellular potency compared to EPI-506 which are also metabolically stable. IND-selection preclinical studies are underway on the most promising Aniten’s with an IND submission planned shortly.

Ronan Le Moigne; Han-Jie Zhou; Nasrin R Mawji; C. Adriana Banuelos; Jun Wang; Kunzhong Jian; Peter Virsik; Raymond J Andersen; Marianne Sadar. Next generation N-terminal domain androgen receptor inhibitors with improved potency and metabolic stability in castration-resistant prostate cancer models. Journal of Clinical Oncology 2019, 37, 220 -220.

Ronan Le Moigne, Han-Jie Zhou, Nasrin R Mawji, C. Adriana Banuelos, Jun Wang, Kunzhong Jian, Peter Virsik, Raymond J Andersen, Marianne Sadar. Next generation N-terminal domain androgen receptor inhibitors with improved potency and metabolic stability in castration-resistant prostate cancer models. Journal of Clinical Oncology. 2019; 37 (7_suppl):220-220.

Ronan Le Moigne; Han-Jie Zhou; Nasrin R Mawji; C. Adriana Banuelos; Jun Wang; Kunzhong Jian; Peter Virsik; Raymond J Andersen; Marianne Sadar. 2019. "Next generation N-terminal domain androgen receptor inhibitors with improved potency and metabolic stability in castration-resistant prostate cancer models." Journal of Clinical Oncology 37, no. 7_suppl: 220-220.

Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375–86. ©2017 AACR.

Ronan Le Moigne; Blake T. Aftab; Stevan Djakovic; Eugen Dhimolea; Eduardo Valle; Megan Murnane; Emily M. King; Ferdie Soriano; Mary-Kamala Menon; Zhi Yong Wu; Stephen T. Wong; Grace J. Lee; Bing Yao; Arun P. Wiita; Christine Lam; Julie Rice; Jinhai Wang; Marta Chesi; P. Leif Bergsagel; Marianne Kraus; Christoph Driessen; Szerenke Kiss Von Soly; F. Michael Yakes; David Wustrow; Laura Shawver; Han-Jie Zhou; Thomas G. Martin; Jeffrey L. Wolf; Constantine S. Mitsiades; Daniel J. Anderson; Mark Rolfe. Data from The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma. 2023 .

Ronan Le Moigne, Blake T. Aftab, Stevan Djakovic, Eugen Dhimolea, Eduardo Valle, Megan Murnane, Emily M. King, Ferdie Soriano, Mary-Kamala Menon, Zhi Yong Wu, Stephen T. Wong, Grace J. Lee, Bing Yao, Arun P. Wiita, Christine Lam, Julie Rice, Jinhai Wang, Marta Chesi, P. Leif Bergsagel, Marianne Kraus, Christoph Driessen, Szerenke Kiss Von Soly, F. Michael Yakes, David Wustrow, Laura Shawver, Han-Jie Zhou, Thomas G. Martin, Jeffrey L. Wolf, Constantine S. Mitsiades, Daniel J. Anderson, Mark Rolfe. Data from The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma. . 2023; ():.

Ronan Le Moigne; Blake T. Aftab; Stevan Djakovic; Eugen Dhimolea; Eduardo Valle; Megan Murnane; Emily M. King; Ferdie Soriano; Mary-Kamala Menon; Zhi Yong Wu; Stephen T. Wong; Grace J. Lee; Bing Yao; Arun P. Wiita; Christine Lam; Julie Rice; Jinhai Wang; Marta Chesi; P. Leif Bergsagel; Marianne Kraus; Christoph Driessen; Szerenke Kiss Von Soly; F. Michael Yakes; David Wustrow; Laura Shawver; Han-Jie Zhou; Thomas G. Martin; Jeffrey L. Wolf; Constantine S. Mitsiades; Daniel J. Anderson; Mark Rolfe. 2023. "Data from The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma." , no. : .

Numerous studies have shown that alteration of actin remodeling plays a pivotal role in the regulation of morphologic and phenotypic changes leading to malignancy. In the present study, we searched for drugs that can regulate actin polymerization and reverse the malignant phenotype in cancer cells. We developed a cell-free high-throughput screening assay for the identification of compounds that induce the actin polymerization in vitro, by fluorescence anisotropy. Then, the potential of the hit compound to restore the actin cytoskeleton and reverse the malignant phenotype was checked in EWS-Fli1-transformed fibroblasts and in B16-F10 melanoma cells. A β-carboline extracted from Peganum harmala (i.e., harmine) is identified as a stimulator of actin polymerization through a mechanism independent of actin binding and requiring intracellular factors involved in a process that regulates actin kinetics. Treatment of malignant cells with non-cytotoxic concentrations of harmine induces the recovery of a non-malignant cell morphology accompanied by reorganization of the actin cytoskeleton, rescued cell–cell adhesion, inhibition of cell motility and loss of anchorage-independent growth. In conclusion, harmine induces the reversion of the malignant phenotype by a process involving the modulation of actin dynamics and is a potential anti-tumor agent acting principally through a non-cytotoxic process.

Ronan Le Moigne; Frédéric Subra; Manale Karam; Christian Auclair. The β-carboline Harmine Induces Actin Dynamic Remodeling and Abrogates the Malignant Phenotype in Tumorigenic Cells. Cells 2020, 9, 1168 .

Ronan Le Moigne, Frédéric Subra, Manale Karam, Christian Auclair. The β-carboline Harmine Induces Actin Dynamic Remodeling and Abrogates the Malignant Phenotype in Tumorigenic Cells. Cells. 2020; 9 (5):1168.

Ronan Le Moigne; Frédéric Subra; Manale Karam; Christian Auclair. 2020. "The β-carboline Harmine Induces Actin Dynamic Remodeling and Abrogates the Malignant Phenotype in Tumorigenic Cells." Cells 9, no. 5: 1168.

Ronan Le Moigne; Han-Jie Zhou; Nasrin R. Mawji; C. Adriana Banuelos; Jun Wang; Kunzhong Jian; Peter Virsik; Raymond J. Andersen; Marianne D. Sadar. MP34-04 A NEW GENERATION OF N-TERMINAL DOMAIN ANDROGEN RECEPTOR INHIBITORS IN CASTRATION-RESISTANT PROSTATE CANCER MODELS. Journal of Urology 2019, 201 .

Ronan Le Moigne, Han-Jie Zhou, Nasrin R. Mawji, C. Adriana Banuelos, Jun Wang, Kunzhong Jian, Peter Virsik, Raymond J. Andersen, Marianne D. Sadar. MP34-04 A NEW GENERATION OF N-TERMINAL DOMAIN ANDROGEN RECEPTOR INHIBITORS IN CASTRATION-RESISTANT PROSTATE CANCER MODELS. Journal of Urology. 2019; 201 (Supplement):.

Ronan Le Moigne; Han-Jie Zhou; Nasrin R. Mawji; C. Adriana Banuelos; Jun Wang; Kunzhong Jian; Peter Virsik; Raymond J. Andersen; Marianne D. Sadar. 2019. "MP34-04 A NEW GENERATION OF N-TERMINAL DOMAIN ANDROGEN RECEPTOR INHIBITORS IN CASTRATION-RESISTANT PROSTATE CANCER MODELS." Journal of Urology 201, no. Supplement: .

Corinne Maurice-Dror; Ronan Le Moigne; Ulka Vaishampayan; Robert B. Montgomery; Michael S. Gordon; Nan Hyung Hong; Leah DiMascio; Frank Perabo; Kim N. Chi. A phase 1 study to assess the safety, pharmacokinetics, and anti-tumor activity of the androgen receptor n-terminal domain inhibitor epi-506 in patients with metastatic castration-resistant prostate cancer. Investigational New Drugs 2021, 40, 322 -329.

Corinne Maurice-Dror, Ronan Le Moigne, Ulka Vaishampayan, Robert B. Montgomery, Michael S. Gordon, Nan Hyung Hong, Leah DiMascio, Frank Perabo, Kim N. Chi. A phase 1 study to assess the safety, pharmacokinetics, and anti-tumor activity of the androgen receptor n-terminal domain inhibitor epi-506 in patients with metastatic castration-resistant prostate cancer. Investigational New Drugs. 2021; 40 (2):322-329.

Corinne Maurice-Dror; Ronan Le Moigne; Ulka Vaishampayan; Robert B. Montgomery; Michael S. Gordon; Nan Hyung Hong; Leah DiMascio; Frank Perabo; Kim N. Chi. 2021. "A phase 1 study to assess the safety, pharmacokinetics, and anti-tumor activity of the androgen receptor n-terminal domain inhibitor epi-506 in patients with metastatic castration-resistant prostate cancer." Investigational New Drugs 40, no. 2: 322-329.

Christos Kyriakopoulos; Gurkamal S. Chatta; Andrew Leonard Laccetti; Nicholas Iannotti; Alexandra Sokolova; Sebastien J. Hotte; Ronald F. Tutrone; Mark Christopher Markowski; Luke T. Nordquist; Roberto Pili; Fred Saad; Jingsong Zhang; Karen Villaluna; Brett Younginger; Ronan Le Moigne; Alessandra Cesano. Phase 1/2 trial of oral EPI-7386 (masofaniten) in combination with enzalutamide (Enz) compared to Enz alone in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase 1 (P1) results and phase 2 (P2) design. Journal of Clinical Oncology 2024, 42, 141 -141.

Christos Kyriakopoulos, Gurkamal S. Chatta, Andrew Leonard Laccetti, Nicholas Iannotti, Alexandra Sokolova, Sebastien J. Hotte, Ronald F. Tutrone, Mark Christopher Markowski, Luke T. Nordquist, Roberto Pili, Fred Saad, Jingsong Zhang, Karen Villaluna, Brett Younginger, Ronan Le Moigne, Alessandra Cesano. Phase 1/2 trial of oral EPI-7386 (masofaniten) in combination with enzalutamide (Enz) compared to Enz alone in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase 1 (P1) results and phase 2 (P2) design. Journal of Clinical Oncology. 2024; 42 (4_suppl):141-141.

Christos Kyriakopoulos; Gurkamal S. Chatta; Andrew Leonard Laccetti; Nicholas Iannotti; Alexandra Sokolova; Sebastien J. Hotte; Ronald F. Tutrone; Mark Christopher Markowski; Luke T. Nordquist; Roberto Pili; Fred Saad; Jingsong Zhang; Karen Villaluna; Brett Younginger; Ronan Le Moigne; Alessandra Cesano. 2024. "Phase 1/2 trial of oral EPI-7386 (masofaniten) in combination with enzalutamide (Enz) compared to Enz alone in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase 1 (P1) results and phase 2 (P2) design." Journal of Clinical Oncology 42, no. 4_suppl: 141-141.

257Background: Aniten compounds bind to the N-terminal domain (NTD) of the androgen receptor (AR) and inhibit AR dependent transcription. EPI-506, the pro-drug of EPI-002, was the first AR NTD inhibitor tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC). The drug was well-tolerated but required high doses. At doses >1280 mg, EPI-506 treatment resulted in PSA declines; however, these were minor and of short duration, reflecting EPI-506’s low potency and short half-life. To understand EPI-506’s metabolic vulnerabilities, patient plasma samples were analyzed to identify metabolites. Methods: PSA serum levels were assessed after a month of dosing. Patient plasma samples were analyzed and pharmacokinetic (PK) parameters calculated. Three plasma samples from patients (one 80 and two 3,600 mg doses), were pooled across timepoints and metabolites were analyzed. EPI-506 metabolism was assessed in in vitro ADME assays and metabolite activity was measured. Results: EPI-002 ...

Ronan Le Moigne; Han-Jie Zhou; Jon K. Obst; C. Adriana Banuelos; Kunzhong Jian; David Williams; Peter Virsik; Raymond J Andersen; Marianne Sadar; Frank Perabo; Kim N. Chi. Lessons learned from the metastatic castration-resistant prostate cancer phase I trial of EPI-506, a first-generation androgen receptor N-terminal domain inhibitor. Journal of Clinical Oncology 2019, 37, 257 -257.

Ronan Le Moigne, Han-Jie Zhou, Jon K. Obst, C. Adriana Banuelos, Kunzhong Jian, David Williams, Peter Virsik, Raymond J Andersen, Marianne Sadar, Frank Perabo, Kim N. Chi. Lessons learned from the metastatic castration-resistant prostate cancer phase I trial of EPI-506, a first-generation androgen receptor N-terminal domain inhibitor. Journal of Clinical Oncology. 2019; 37 (7_suppl):257-257.

Ronan Le Moigne; Han-Jie Zhou; Jon K. Obst; C. Adriana Banuelos; Kunzhong Jian; David Williams; Peter Virsik; Raymond J Andersen; Marianne Sadar; Frank Perabo; Kim N. Chi. 2019. "Lessons learned from the metastatic castration-resistant prostate cancer phase I trial of EPI-506, a first-generation androgen receptor N-terminal domain inhibitor." Journal of Clinical Oncology 37, no. 7_suppl: 257-257.