erteberel (LY500307) / Eli Lilly - LARVOL DELTA

ERβ mediates sex-specific protection in the App-NL-G-F mouse model of Alzheimer's disease. (PubMed, Biol Sex Differ) - "Combined, we provide new understanding to the sex differences in AD by demonstrating that ERβ protects against AD pathology differently in males and females, warranting reassessment of ERβ in combating AD."

Journal • Preclinical • Alzheimer's Disease • Amyloidosis • CNS Disorders • Inflammation • ER

Potent estrogen receptor β agonists with inhibitory activity in vitro, fail to suppress xenografts of endocrine-resistant cyclin-dependent kinase 4/6 inhibitor-resistant breast cancer cells. (PubMed, Front Oncol) - "Here, we used fulvestrant- and abemaciclib-resistant T47D-derived cell line xenografts to determine the efficacy of the combination of OSU-ERβ-12 and LY500307 with tamoxifen in vivo. Despite efficacy in vitro, treatments failed to reduce xenograft tumor volumes. Hence, we conclude that this treatment strategy lacks direct cancer cell-intrinsic cytotoxic efficacy in vivo."

Journal • Preclinical • Breast Cancer • Endocrine Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Estrogen Receptor Βeta Stimulation as a Possible Novel Therapeutic Target for Cutaneous T-Cell Lymphoma. (PubMed, Blood Adv) - "Furthermore, LY500307 treatment significantly reduced tumor growth in a CTCL xenograft mouse model without notable toxicity. These findings suggest LY500307 as a promising therapeutic agent for CTCL, warranting further clinical investigation, including the potential for topical applications."

Journal • Cutaneous T-cell Lymphoma • Dermatology • Hematological Disorders • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • ER

Effects of an ER Beta Agonist (Lilly Compound LY500307) on Estradiol-Withdrawal-Induced Mood Symptoms in Women With Past Perimenopausal Depression (clinicaltrials.gov) - P2 | N=68 | Completed | Sponsor: National Institute of Mental Health (NIMH) | Recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Sep 2024 | Trial primary completion date: Dec 2025 ➔ Sep 2024

Trial completion • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Mood Disorders • Psychiatry

ERβ mediates sex-specific protection in the App-NL-G-F mouse model of Alzheimer's disease. (PubMed, bioRxiv) - "We treated male and female App NL-G-F mice with the selective ERβ agonist LY500307 and subset of the females was ovariectomized prior to treatment...We further identify that ERβ does not alter APP processing, but rather exerts its protection through amyloid scavenging that at least in part is mediated via microglia in a sex-specific manner. Combined, we provide new understanding to the sex differences in AD by demonstrating that ERβ protects against AD pathology differently in males and females, warranting reassessment of ERβ in combating AD."

Journal • Preclinical • Alzheimer's Disease • Amyloidosis • CNS Disorders • Inflammation • ER

Activation of ERβ hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer. (PubMed, Proc Natl Acad Sci U S A) - "In this study, we demonstrated that a specific ERβ agonist, LY500307, potently induces R-loop formation and DNA damage in TNBC cells...In clinical samples including 115 patients from The Cancer Genome Atlas (TCGA) and 32 patients from an in-house cohort, we found a close correlation in the expression of ESR2 and U2AF1 in TNBC patients. Collectively, our study has unraveled the molecular mechanisms that explain the therapeutic effects of ERβ activation in TNBC, which provides rationale for ERβ activation-based single or combined therapy for patients with TNBC."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • U2AF1

Pharmacological inhibition of KDM1A/LSD1 enhances estrogen receptor beta-mediated tumor suppression in ovarian cancer. (PubMed, Cancer Lett) - "Importantly, KDM1A-KO or -KD enhanced the efficacy of ERβ agonist LY500307, and the combination of KDM1A inhibitor (KDM1Ai) NCD38 with ERβ agonist synergistically reduced the cell viability, colony formation, and invasion of OCa cells...Our results demonstrate that KDM1A regulates ERβ expression/functions, and its inhibition improves ERβ mediated tumor suppression. Overall, our findings suggest that KDM1Ai and ERβ agonist combination therapy is a promising strategy for OCa."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • ER • KDM1A

Effect of OSU-ERß-12, a carborane-based ERß-selective agonist, on hepatic fibrosis and NASH (ENDO 2023) - "Efficacy of ERß-12 was tested in the CCl4 model of hepatic fibrosis by administering CCl4 to mice over 4 weeks at which point intervention with estradiol, LY500307 (LY) and ERß-12 started...This effect was reversed with the pan-ER antagonist fulvestrant. Conclusion. These data suggest that ERß agonism inhibits TGFß-mediated liver fibrosis and supports further investigation of ERß-targeted therapeutic candidates."

Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Oncology • Solid Tumor • COL1A1

Effect of OSU-ERß-12, a carborane-based ERß-selective agonist, on hepatic fibrosis and NASH (ENDO 2023) - "Efficacy of ERß-12 was tested in the CCl4 model of hepatic fibrosis by administering CCl4 to mice over 4 weeks at which point intervention with estradiol, LY500307 (LY) and ERß-12 started...This effect was reversed with the pan-ER antagonist fulvestrant...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*"

Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Oncology • Solid Tumor • COL1A1

Effects of an ER Beta Agonist (Lilly Compound LY500307) on Estradiol-Withdrawal-Induced Mood Symptoms in Women With Past Perimenopausal Depression (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: National Institute of Mental Health (NIMH) | N=54 ➔ 80

Enrollment change • CNS Disorders • Depression • Mood Disorders • Psychiatry

Therapeutic Targeting of Ovarian Cancer Stem Cells Using Estrogen Receptor Beta Agonist. (PubMed, Int J Mol Sci) - "Importantly, treatment of LY500307 significantly attenuated the tumor-initiating capacity of OCSCs in orthotopic OCa murine xenograft models. Our results demonstrate that ERβ agonist LY500307 is highly efficacious in reducing the stemness and promoting apoptosis of OCSCs and shows significant promise as a novel therapeutic agent in treating OCa."

Cancer stem cells • Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • CASP3 • CDKN1A • ER • NANOG • POU5F1 • SOX2

Ahi1 regulates serotonin production by the GR/ERβ/TPH2 pathway involving sexual differences in depressive behaviors. (PubMed, Cell Commun Signal) - "In conclusion, although it is unclear how Ahi1 controls E2 secretion in the brain, our findings demonstrate that Ahi1 regulates serotonin production by the GR/ERβ/TPH2 pathway in the brain and possibly involves the regulation on sex differences in depressive behaviors. Video Abstract."

Journal • CNS Disorders • Depression • Mental Retardation • Psychiatry

Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer. (PubMed, Front Oncol) - "The viability of ERα+ breast cancer cell lines upon treatments with specific ERβ agonists, including OSU-ERb-12 and LY500307, was assessed...Lastly, ESR2 (ERβ gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ERα+/HER2- breast cancer samples. Our results demonstrate that highly selective ERβ agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CCND1 • ER • FOXO3 • HER-2

Different Susceptibilities of Human Melanoma Cell Lines to G2/M Blockage and Cell Death Activation in Response to the Estrogen Receptor β agonist LY500307. (PubMed, J Cancer) - "Indeed, the ERβ agonist affects melanoma migration, inducing a reversion of the epithelial-mesenchymal transition, more evident in a low aggressive primary melanoma cell line. These results demonstrate the capability of LY500307 to reduce melanoma malignancy, counteracting cell viability and dissemination, overall suggesting a possible future use of LY500307 in personalized combined therapy."

Journal • Preclinical • Melanoma • Oncology • Solid Tumor • CASP3 • ER • NRAS • PARP1

Histone deacetylase inhibitors enhance estrogen receptor beta expression and augment agonist-mediated tumor suppression in glioblastoma. (PubMed, Neurooncol Adv) - "Of all inhibitors tested, HDACi (panobinostat and romidepsin) showed the potential to increase the expression of ERβ in GBM cells. In orthotopic GBM model, combination therapy of panobinostat and LY500307 enhanced survival of tumor-bearing mice. Our results suggest that the combination therapy of HDACi and LY500307 provides therapeutic utility in overcoming the suppression of ERβ expression that commonly occurs in GBM progression."

Epigenetic controller • Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • ER

Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells. (PubMed, Cell Death Discov) - "Furthermore, our data demonstrated that mitochondrial ER-β can be successfully targeted by the selective ER-β agonist Erteberel. Thus, our findings provide novel findings on mitochondrial estrogen signaling in breast cancer cells and suggest the implementation of the dynamic BH3 technique as a tool to predict acquired endocrine therapy resistance."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER

Effects of an ER Beta Agonist (Lilly Compound LY500307) on Estradiol-Withdrawal-Induced Mood Symptoms in Women With Past Perimenopausal Depression (clinicaltrials.gov) - P2; N=54; Recruiting; Sponsor: National Institute of Mental Health (NIMH); Trial completion date: Dec 2022 ➔ Dec 2025; Trial primary completion date: Dec 2022 ➔ Dec 2025

Trial completion date • Trial primary completion date • CNS Disorders • Depression • Mood Disorders • Psychiatry

Activation of estrogen receptor beta signaling reduces stemness of glioma stem cells. (PubMed, Stem Cells) - "Here, we examined whether ERβ modulates GSCs stemness and tested the utility of two ERβ selective agonists (LY500307 and Liquiritigenin) to reduce the stemness of GSCs...Mechanistically, ERβ activation reduced glutamate receptor signaling in GSCs, reduced the tumor progression and improved the survival in orthotopic murine models. This study proposes that ERβ agonists may represent promising therapeutic agents for eliminating GSCs, and thereby improving the overall survival of GBM patients."

Journal • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Estrogen receptoragonists suppress the growth and progression of mammary tumors in immune-competent mouse models (AACR 2018) - "Our results demonstrated that LY500307 inhibited the tumor growth and the effect was more pronounce in combination with aromatase inhibitor letrozole. Our results suggested that ER agonists have potential to prevent the progression mammary tumors in immunocompetent hosts."

Preclinical • Hormone Receptor Breast Cancer

[VIRTUAL] SELECTIVE ESTROGEN RECEPTOR MODULATOR, OSU-ERB-12, AMELIORATES PRECLINICAL MODELS OF HEPATIC FIBROSIS AND NASH. (AASLD 2020) - "Transfected cells were exposed to escalating doses of estradiol (E2), positive control ERβ-selective ligand LY500307 (LY) or ERb-12... Preclinical testing establishes OSU-ERb-12 as an exceptional NASH therapeutic candidate that demonstrates remarkable efficacy without eliciting predictable toxicities."

Preclinical • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis • CCL4 • ER

[VIRTUAL] Estrogen Receptor Beta Stimulation as a Possible Novel Therapeutic Target for Cutaneous T-Cell Lymphoma (ADO 2020) - "However, targeting ERβ with the selective synthetic ERβ agonists LY500307, ERB-041 and the phytoestrogen genistein significantly reduced cell proliferation of all four CTCL cell lines in a dose-dependent manner... Altogether, our preclinical results suggest that targeting ERβ with selective agonists might be potential novelty in the treatment of CTCL."

Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • AR • ER

Pharmacological Activation of Estrogen Receptor Beta Overcomes Tumor Resistance to Immune Checkpoint Blockade Therapy. (PubMed, iScience) - "Mechanistically, LY500307 treatment reduced tumor-derived CSF1 and decreased infiltration of CSF1R MDSCs in the tumor bed. CSF1 released by tumor cells induced CSF1R MDSC chemotaxis in vitro and blockade of CSF1R demonstrated similar therapeutic effects as ERβ activation in vivo. Collectively, our study proved combined treatment of ERβ agonist and PD-1 antibody reduced MDSC infiltration in the tumor and enhanced tumor response to ICB therapy."

Checkpoint inhibition • Journal • Immune Modulation • Immunology • Inflammation • Oncology • CSF1R • ER

Effects of an ER Beta Agonist (Lilly Compound LY500307) on Estradiol-Withdrawal-Induced Mood Symptoms in Women With Past Perimenopausal Depression (clinicaltrials.gov) - P2; N=54; Recruiting; Sponsor: National Institute of Mental Health (NIMH); Trial completion date: Sep 2024 ➔ Dec 2022

Clinical • Trial completion date • CNS Disorders • Depression • Mood Disorders

The efficacy and safety of a selective estrogen receptor beta agonist (LY500307) for negative symptoms and cognitive impairment associated with schizophrenia (clinicaltrials.gov) - P2, N=90; Recruiting; New P2 trial.

New P2 trial • Schizophrenia

Population pharmacokinetic/pharmacodynamic assessment of pharmacological effect of a selective estrogen receptor β agonist on total testosterone in healthy men. - Clin Pharmacol Drug Dev - "Population PK/PD modeling is a highly sensitive tool to detect exposure-response relationships on top of the complicated and highly variable circadian rhythm of TT."

Journal • Biosimilar