EPI-7170 / ESSA Pharma - LARVOL DELTA

Emerging role of HIC1 in prostate cancer progression and therapeutic response: A novel perspective. (PubMed, J Cell Commun Signal) - "Conversely, AR and IRS2 inhibitors like EPI-7170 and NT157 negatively affected PCa progression. These results underscore HIC1's potential as a therapeutic target in PCa, offering new insights into its role in cancer biology and treatment."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CASP3 • HIC1 • IRS2

The Androgen Receptor-Serum Response Factor Network As a Pharmacological Target in Castration Resistant Prostate Cancer. (EACR 2025) - "Small molecule inhibitors include SRF inhibitors (CCG1423, Lestaurtinib), AR/ARv7 inhibitors (Enzalutamide, EPI7170) and common co-factor inhibitors (VER-15508, JG-98, Ganetespib, Ipatasertib, Alpelisib). To conclude, our results indicate that targeting the AR-SRF intracellular network holds promise as a treatment option for patients with CRPC. Combination treatments were shown to bypass resistance mechanisms in our CRPC cell line models and are synergistic at lower concentrations. Furthermore, by studying the proteomic and phosphor-proteomic landscape before and after treatments, we can further understand disease and resistance mechanisms in PCa as well as find potential novel targets which can be used for the disease."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CDC37 • HSP90AA1

Covalent Adducts Formed by the Androgen Receptor Transactivation Domain and Small Molecule Drugs Remain Disordered. (PubMed, J Chem Inf Model) - "Here, we utilize all-atom molecular dynamics computer simulations to simulate covalent adducts of small molecule ligands EPI-002 and EPI-7170 bound to the disordered androgen receptor transactivation domain...We compare the populations of protein-ligand interactions observed in covalent adduct ensembles to those observed in non-covalent ligand-bound ensembles and find substantial differences. Our results provide atomically detailed descriptions of covalent adducts formed by small molecules and an intrinsically disordered protein and suggest strategies for developing more potent covalent inhibitors of intrinsically disordered proteins."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Covalent adducts formed by the androgen receptor transactivation domain and small molecule drugs remain disordered. (PubMed, bioRxiv) - "Here, we utilize all-atom molecular dynamics computer simulations to simulate covalent adducts of the small molecule ligands EPI-002 and EPI-7170 bound to the disordered androgen receptor transactivation domain...We compare the populations of protein-ligand interactions observed in covalent adduct ensembles to those observed in non-covalent ligand-bound ensembles and find substantial differences. Our results provide atomically detailed descriptions of covalent adducts formed by small molecules and an intrinsically disordered protein and suggest strategies for developing more potent covalent inhibitors of intrinsically disordered proteins."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

A Mechanism of Resistance to Novel Inhibitors of the N-Terminal Domain of Androgen Receptor (ENDO 2023) - "Importantly, the ability of another EPI analog, EPI-7170, to decrease AR-N/C interaction was not significantly impacted by W435L. Tryptophan mutations in the EPI-7386 binding site are predictive of resistance to this specific antagonist and do not broadly apply to the entire class of EPI analogs. Key differences were revealed between AR-LBD and AR-NTD inhibitors that support the recruitment of different tau regions in the NTD."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

A Mechanism of Resistance to Novel Inhibitors of the N-Terminal Domain of Androgen Receptor (ENDO 2023) - "Importantly, the ability of another EPI analog, EPI-7170, to decrease AR-N/C interaction was not significantly impacted by W435L. Tryptophan mutations in the EPI-7386 binding site are predictive of resistance to this specific antagonist and do not broadly apply to the entire class of EPI analogs. Key differences were revealed between AR-LBD and AR-NTD inhibitors that support the recruitment of different tau regions in the NTD.*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Molecular characterization of next generation AR-NTD inhibitors (AACR-NCI-EORTC 2022) - P1, P1/2 | "Ralaniten acetate (EPI-506, NCT02606123) and next generation EPI-7386 (NCT04421222) remain the only AR-NTD inhibitors to have progressed to clinical trials. Here we characterize the molecular profile of several next generation AR-NTD inhibitors compared against traditional AR-LBD antagonist enzalutamide (ENZA). LNCaP and LN95 cells treated with EPI-002, EPI-7170 or ENZA were subjected to RNA-seq to identify differences in mechanisms of action for each class of inhibitor... We identified clear differences in the mechanisms of action between traditional AR-LBD inhibitor enzalutamide and AR-NTD inhibitors; in terms of AR-regulated gene expression, disruptions to the cell cycle and DNA damage response. 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)."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • NCOR1 • TBL1XR1

Small molecules targeting the disordered transactivation domain of the androgen receptor induce the formation of collapsed helical states. (PubMed, Nat Commun) - "We find that EPI-7170 binds androgen receptor more tightly than EPI-002 and we identify a network of intermolecular interactions that drives higher affinity binding. Our results suggest strategies for developing more potent androgen receptor inhibitors and general strategies for disordered protein drug design."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with ralaniten analogues for the treatment of androgen receptor-positive prostate and breast cancers. (PubMed, Mol Cancer Ther) - "Androgen receptor (AR) has essential roles in the growth of prostate cancer and some breast cancers. Importantly, sequential combination treatments with palbociclib administered first then followed by EPI-7170, resulted in more cells accumulating in G1 and less cells in S phase than concomitant combination which was presumably because each inhibitor has a unique mechanism in modulating the cell cycle in cancer cells. Together these data support that the combination therapy was more effective than individual monotherapies to reduce tumor growth by targeting different phases of the cell cycle."

Combination therapy • Journal • Breast Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR