AZD9496 / AstraZeneca - LARVOL DELTA

Estradiol conjugation to estrogen receptorα upregulates Brms1 expression mediating M2 polarization of alveolar macrophages and exacerbating airway inflammation in asthmatic mice. (PubMed, Mol Immunol) - "The use of ERα antagonist AZD9496 reduced the effect of E2 on the promotion of M2 polarization in AMs...Interference with Brms1 mRNA production reduced the gene expression of Arg1 and YM1 in AMs undergoing M2 polarization after E2 stimulation. In summary, E2 exacerbates airway inflammation in asthmatic mice and binds to ERα, upregulating Brms1 expression and mediating M2 polarization of AMs."

Journal • Preclinical • Asthma • Breast Cancer • Hormone Receptor Breast Cancer • Immunology • Inflammation • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • ARG1 • BRMS1 • ER • MRC1

Asymptotic analysis of mathematical model describing a new treatment of breast cancer using AZD9496 and palbociclib. (PubMed, Front Oncol) - "The stability of the equilibrium points is investigated, which is essential from a practical perspective. Investigating the stability of the equilibrium points allows determination of when the tumor does not continue to develop and thereby allows adjustment of treatment continuation."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

Tianxiangdan (TXD) alleviates myocardial ischemia reperfusion-induced ferroptosis through the activation of estrogen receptor alpha (ERα). (PubMed, Chin J Nat Med) - "To examine if TXD reduces I/R injury through ERα, an AZD group (300 nmol·L-1 AZD9496 and 15% TXD serum) was compared to a TXD group (15% TXD serum)...TXD activates the ERα signaling pathway, promoting protection against I/R-induced myocardial cell ferroptosis. This study provides evidence supporting TXD use for myocardial ischemia treatment, particularly in older female patients who may benefit from its therapeutic outcomes."

Journal • Cardiovascular • Myocardial Ischemia • Reperfusion Injury • ER • GPX4

Construction and clinical significance of prognostic risk markers based on cancer driver genes in lung adenocarcinoma. (PubMed, Clin Transl Oncol) - "This study identified 11 effective biomarkers, DE-CDGs, which can predict LUAD prognosis and explored the biological significance of CDGs in LUAD prognosis, immunotherapy, and treatment."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

High Oestrogen receptor alpha expression correlates with adverse prognosis and promotes metastasis in colorectal cancer. (PubMed, Cell Commun Signal) - "Pharmacological blockade or siRNA silencing of ERα limited cell survival and metastasis while restoring tight junction protein expression. In conclusion, these findings highlight the potential of ERα as a prognostic marker for CRC and its role in metastasis."

Journal • Colon Cancer • Colorectal Cancer • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Immunology • Oncology • Solid Tumor • ER • OCLN • TJP1

A new treatment for breast cancer using a combination of two drugs: AZD9496 and palbociclib. (PubMed, Sci Rep) - "The significant advantage of this method is that the mathematical model does not have to contain a small parameter (as is standard in perturbation theory). However, it is possible to artificially introduce a small parameter into the system of equations, making it possible to study the model using asymptotic methods."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CDK4 • CDK6

Enhancing endoplasmic reticulum stress for treating endocrine therapy resistant breast cancers driven by mutant estrogen receptors (SABCS 2023) - "To enable clinical translation of ERX-41, we performed lead optimization, followed by preclinical and IND-enabling studies...Explants, organoids, cell line-(CDX) and patient-derived (PDX) xenografts were used to test the ex vivo and in vivo effectiveness of our lead compound as a monotherapy and in combination with abemaciclib...We have shown that this capacity of ERX-315 to induce endoplasmic reticulum stress is unique among drugs targeting ERα, including selective ERα modulators and degraders, such as GDC-0180, AZD-9496 and fulvestrant... We have identified a lead compound ERX-315, which represents a novel class of agent that induce catastrophic levels of ER stress resulting in cancer cell death and that can effectively work against multiple forms of ETR-BC, including those driven by MT-ERα. Preclinical studies, GMP manufacturing, formulation and IND-enabling studies are being completed in time for the commencement of the phase I clinical trial by Q1 2024."

Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

A pre-surgical, window of opportunity study comparing the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2- primary breast cancer (SABCS 2019) - P1; "AZD9496 250 mg BID reduced ER, PR and Ki-67 expression, and as such, is the first pre surgical study to demonstrate an oral SERD impacting its key biological targets. These reductions were not superior to the FULV clinically approved dose, which performed as expected based on historical data. Pre-surgical studies represent an important method to test the proof of mechanism of novel SERDs early in clinical development."

Clinical • ER • HER2 • PGR

[VIRTUAL] Discovery of AZD9833, an oral small molecule selective degrader of the estrogen receptor (SERD) (AACR-II 2020) - P1 | "Anti-hormonal therapies that block ER function directly (e.g. tamoxifen) or therapies that block the production of estrogen itself (e.g., aromatase inhibitors) have proven to be effective treatments of the disease. Further advances in disease control have been made with the development of the Selective Estrogen Receptor Degrader (SERD) fulvestrant, which both antagonizes ERα-driven tumor cell growth and causes degradation of the ERα receptor. The first-generation oral SERDs, including AZD9496, showed full ER degradation in MCF-7 cells but incomplete ER degradation in other cell lines, and partial agonism...Furthermore, in an ESR1 wild-type and an ESR1 D538G PDX model, AZD9833 demonstrated combinatorial benefit with palbociclib. Based on this preclinical data AZD9833 has progressed into a multi-stage monotherapy and palbociclib combination First Time in Patient clinical trial, SERENA-1 (NCT03616587)."

Breast Cancer • Endometrial Cancer • Gynecologic Cancers • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER

Comparative Efficacy of AZD9496 and Fulvestrant on the Growth of Pituitary Adenoma via Blocking JAK2/STAT5B Pathway. (PubMed, J Cancer) - "Mechanically, the AZD9496 and fulvestrant significantly blocked JAK2/STAT5B pathway in GT1-1 cells and xenograft mice. Our results provide substantial evidence for the subsequent clinical use of AZD9496 in the treatment of patients with pituitary adenoma."

Journal • Brain Cancer • Oncology • Pituitary Gland Carcinoma • Solid Tumor • STAT5B

PBX1 Participates in Estrogen-Mediated Bladder Cancer Progression and Chemo-Resistance Affecting Estrogen Receptors. (PubMed, Curr Cancer Drug Targets) - "This study revealed that PBX1 participated in estrogen mediated BCa progression and chemo-resistance through binding and activating estrogen receptors. Hence, PBX1 may serve as a potential prognostic and therapeutic target for BCa treatment."

Journal • Bladder Cancer • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Urothelial Cancer • ER • PBX1

Inhibition of estrogen receptor signaling as a strategy for radiosensitization of ER+ breast cancers (AACR 2022) - "Here we assessed the efficacy and mechanism of ER-mediated radiosensitization using various pharmacologic approaches in ER+ BC. Radiosensitization with ER inhibitors (tamoxifen [TAM], fulvestrant [FULV], AZD9496) was assessed using clonogenic survival assays. Our data suggest that TAM, FULV, or AZD9496 can radiosensitize ER+ breast tumors, and these agents with RT may be more effective for radiosensitization. This work also supports further clinical investigation of the timing of RT for patients receiving ET, including using ET during RT, especially as initiating ET prior to RT has been increasingly utilized as a bridging therapy followed by concurrent ET+RT during the COVID-19 pandemic."

Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • ER • RAD51

Molecular docking and optical sensor studies based on 2,4-diamino pyrimidine-5-carbonitriles for detection of Hg. (PubMed, Environ Res) - "The molecular docking of 2,4-diamino-6-(phenyl)pyrimidine-5-carbonitrile compound has been done with the protein selective estrogen receptor 5ACC complexed with (Azd9496), Human Anaplastic Lymphoma Kinase Pdb; 2xp2 complex with crizotinib (PF-02341066) and human wee1 kinase Pdb; 5vc3 complexed with bosutinib. The ligands 2,4-diamino-6-(phenyl)pyrimidine-5-carbonitrile generate very good docking results with the protein Pdb; 2xp2, which is responsible for effective tumor growth inhibition."

Journal • Oncology • ALK • ER

Estrogen receptor inhibition mediates radiosensitization of ER-positive breast cancer models. (PubMed, NPJ Breast Cancer) - "Clonogenic survival assays were performed using variable pre- and post-treatment conditions to assess radiosensitization with estradiol, estrogen deprivation, tamoxifen, fulvestrant, or AZD9496 in ER+ breast cancer cell lines. Using an MCF-7 xenograft model, concurrent treatment with tamoxifen and RT was synergistic and resulted in a significant decrease in tumor volume and a delay in time to tumor doubling without significant toxicity. These findings provide preclinical evidence that concurrent treatment with ET and RT may be an effective radiosensitization strategy."

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

C–H radioiodination of small molecule drugs (ACS-Sp 2022) - "We then performed the radioiodination of small molecule drugs under identical conditions; GSK923295, AZD9496, mivebresib, GSK2879552, sotorasib, tozasertib, KU-55933, and venetoclax. Radiochemical conversions of all small molecule drugs ranged from 70-90%, with the exception of sotorasib, which gave a lower yield of 40% and a mixture of ortho- para- substituents on the phenol moiety. In summary, we identified a new method for C–H radioiodination of small molecule drugs under mild conditions that enables access to new radiopharmaceuticals."

Investigation of neratinib and endocrine therapy combinations in HER2 positive breast cancer models (SABCS 2021) - "Fulvestrant (SERD, #S1191), AZD9496 (novel, orally bioavailable SERD, #S8372) and ribociclib (CDK4/6 inhibitor, #S7440) were obtained from Selleckchem. Using publicly available data, our results highlight the positive impact ET has on HER2+ breast cancer survival outcome. In vitro data supports the combination of novel SERDs and neratinib as a therapeutic strategy that warrants further investigation in HER2+/ER+ breast cancer."

Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection. (PubMed, Mol Oncol) - "Whole blood (WB) specimens were collected at serial time points from patients with advanced ER-POS/HER2-negative (NEG) advanced breast cancer in a phase I trial of AZD9496, an oral selective ER degrader (SERD) ET...Intra-patient, inter-CTC genomic heterogeneity was observed, at times between timepoints, in subclonal alterations. Our analysis suggests that serial monitoring of the CTC genome is feasible and should enable real-time tracking of tumor evolution during progression, permitting more combination precision medicine interventions."

Biomarker • 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 • CTCs • ER • FGFR2 • HER-2 • PIK3CA

Syringaresinol attenuates sepsis-induced cardiac dysfunction by inhibiting inflammation and pyroptosis in mice. (PubMed, Eur J Pharmacol) - "Furthermore, molecular docking analysis predicted that there is high affinity between SYR and estrogen receptor (ER), ER inhibitor ICI182780, the specific ERβ inhibitor PHTP and the specific ERαinhibitor AZD9496 were used to examine the role of ER in the protective effect of SYR against SICD, and the results suggested that ER activation was essential for the cardioprotective function of SYR. In conclusion, SYR ameliorates SICD via the ER/SIRT1/NLRP3/GSDMD pathway."

Journal • Preclinical • Immunology • Infectious Disease • Inflammation • Septic Shock • NLRP3

[VIRTUAL] Monitoring circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) genomic alterations in ER positive (POS)/HER2 negative (NEG) advanced breast cancer during endocrine therapy: correlative study of AZD9496 oral SERD phase I trial (AACR 2021) - "Serial monitoring of CTC and ctDNA genomic alterations is feasible and should enable real-time tracking of response/progression, tumor evolution and opportunities for precision medicine interventions."

Circulating tumor DNA • P1 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRAF • ER • FGFR2 • HER-2 • PIK3CA

Dynamics-Based Discovery of Novel, Potent Benzoic Acid Derivatives as Orally Bioavailable Selective Estrogen Receptor Degraders for ERα+ Breast Cancer. (PubMed, J Med Chem) - "SAR studies revealed that while the acrylic acid moiety of AZD9496 is scaffold hopping into benzoic acid, compound D24 exhibits potent binding affinity with ERα, good degradation efficacy of ERα, and inhibitory effect against the MCF-7 breast cancer cell line. Besides, D24 also displays good antitumor efficacy in the MCF-7 human breast cancer xenograft model in vivo, favorable pharmacokinetic properties, excellent druggability, and good safety property, making D24 as a promising drug candidate of SERD for further evaluation."

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

[VIRTUAL] Optimizing treatment strategy for NF1-depleted estrogen receptor positive breast cancer (AACR 2021) - "NF1 loss enhanced ER transcription causing resistance to tamoxifen and aromatase inhibition.Approach and In this study, we examined patient data from TCGA cohort and found that low NF1 mRNA levels associated with recurrence in luminal breast cancer, particularly in the luminal B subtype...ER+ NF1-depleted breast cancer cells responded initially to a selective ER degrader (SERD), such as fulvestrant and an oral SERD AZD9496, but acquired resistance with prolonged treatment. The loss of the full length NF1 can stimulate both ER and Ras signaling, and it is possible to efficiently treat ER+ NF1-depleted breast cancer by a SERD, in combination with CDK4/6 inhibitor."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • NF1

Isobavachalcone prevents osteoporosis by suppressing activation of ERK and NF-κB pathways and M1 polarization of macrophages. (PubMed, Int Immunopharmacol) - "However, the impact of ISO in these molecules is eliminated by the application of ERα antagonist AZD9496.We further verified pharmacological effects of ISO in ovariectomized osteoporotic mice, and ISO significantly prevented bone loss and decreased M1 polarization of macrophages from marrow and spleen. Collectively, our data suggest that ISO prevents osteoporosis via suppressing activation of ERK and NF-κB signaling pathways as well as M1 polarization of macrophages."

Journal • Osteoporosis • Rheumatology • ER • MMP9

Pharmacologic and PK/PD study of D-0502: An orally bioavailable SERD with potent antitumor activity in ER-positive breast cancer cell lines and xenograft models (AACR 2018) - "...Endocrine therapy such as selective estrogen receptor degrader (SERD) fulvestrant has been used effectively to extend the life of ER+ breast cancer patients, either alone or in combination with CDK4/6 inhibitor (palbociclib or abemaciclib)...In addition, patients relapsed after prolonged endocrine therapy with aromatase inhibitors such as letrozole and anastrozole due to emergence of ER mutations...Comparison of various SERD molecules showed our candidate has more potent antitumor activity in MCF-7 xenograft model than GDC-0810, AZD9496 and fulvestrant. More importantly, drug metabolism and pharmacokinetic (PK) studies both in vitro and in vivo demonstrated that our SERD molecule D-0502 exhibits superior PK profiles suitable for clinical development."

Preclinical • Hormone Receptor Breast Cancer

"Looks like $AZN discontinued its ph1 SERD AZD9496. Relevant for $SNY & $RHHBY" (@JacobPlieth)

High Sensitivity Detection of a Solubility Limiting Surface Transformation of Drug Particles by DNP SENS. (PubMed, J Pharm Sci) - "The amorphous form of the API has distinguishable C chemical shifts when compared to the salt form under various acidic conditions. The predominant form in frozen particles of AZD9496 is the salt, and we provide evidence to suggest that the amorphous layer at the surface is mainly made up of the dissociated free form."

Journal