NSC668394 / Georgetown University - LARVOL DELTA

Extra-ciliary role for polycystins in regulation of Ezrin and renal tubular morphology. (PubMed, bioRxiv) - "A specific ERM phosphorylation inhibitor, NSC668394, phenocopied the increased circularity observed in the Pkd1 knockout spheroids, as did inhibition of PKC activity, implicating the polycystin complex in regulating Ezrin phosphorylation. Our data strongly support a role for the polycystin complex in regulating renal cell and tubular shape via interactions with the ERM protein Ezrin, interactions that do not require trafficking to the primary cilium."

Journal • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • EZR • PKD1 • PRKD1 • TJP1

Pharmacological inhibition of ezrin reduces proliferative and invasive phenotype in acute lymphoblastic leukemia cells. (PubMed, Eur J Pharmacol) - "NSC305787 induces a dose-dependent reduction in ALL cell viability, and is more potent than a related EZR inhibitor, NSC668394. Notably, NSC305787 shows heightened potency in ALL cells, suggesting its potential as a targeted therapy. In conclusion, our results report high EZR expression in adult ALL patients and support NSC305787 as a promising targeted therapy for ALL that should be further explored."

Journal • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • EZR

Multi-omics profiling of chemotactic characteristics of brain microglia and astrocytoma (AACR 2024) - "To study the role of RDX in chemoattraction, the inhibitor-NSC668394 suppressed collision formation and migration in BV2 cells in vitro by down-regulating F-actin. Additionally, it suppressed macrophage infiltration in infiltrating islands in vivo of intracranial tumor-bearing mice. These findings provide evidence for the role of resident cells in mediating tumor development and invasiveness and suggest that potential interacting molecules may be a strategy for controlling tumor growth by regulating the infiltration of tumor-associated microglia in the brain tumor microenvironment."

Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Multi-omics profiling of chemotactic characteristics of brain microglia and astrocytoma. (PubMed, Life Sci) - "To study the role of RDX in chemoattraction, the inhibitor-NSC668394 suppressed collision formation and migration in BV2 cells in vitro by down-regulating F-actin. Additionally, it suppressed macrophage infiltration in infiltrating islands in vivo of intracranial tumor-bearing mice. These findings provide evidence for the role of resident cells in mediating tumor development and invasiveness and suggest that potential interacting molecules may be a strategy for controlling tumor growth by regulating the infiltration of tumor-associated microglia in the brain tumor microenvironment."

Journal • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Hypoxia enhances interactions between Na/H exchanger isoform 1 and actin filaments via ezrin in pulmonary vascular smooth muscle. (PubMed, Front Physiol) - "Overexpression of wild-type human NHE1 in the absence of hypoxia was sufficient to induce PASMC migration and proliferation, whereas inhibiting ezrin phosphorylation with NSC668394 suppressed NHE1/SMA co-localization and migration in hypoxic PASMCs...From these results, we conclude that hypoxic exposure increases ezrin phosphorylation in PASMCs, leading to enhanced ezrin/NHE1/SMA interaction. We further speculate that these interactions promote anchoring of the actin cytoskeleton to the membrane to facilitate the changes in cell movement and shape required for migration and proliferation."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • EZR

Targeting the Ezrin Adaptor Protein Sensitizes Metastatic Breast Cancer Cells to Chemotherapy and Reduces Neoadjuvant Therapy-induced Metastasis. (PubMed, Cancer Res Commun) - "In this study, we show that upregulating or downregulating ezrin expression modifies the sensitivity of breast cancer cells to doxorubicin and docetaxel treatment in vitro and is associated with changes in PI3K/Akt and NFκB pathway activation. In addition, we tested the effects of systemic treatment with a small-molecule ezrin inhibitor, NSC668394, on lung metastatic burden in vivo as a monotherapy, or in combination with anthracycline- or taxane-based chemotherapy treatment...Taken together, our findings demonstrate the impact of anti-ezrin treatment in modulating response to chemotherapy in breast cancer cells as well as the efficacy of anti-ezrin treatment in combination with chemotherapy at reducing metastatic burden. This work provides preclinical evidence for combining anti-ezrin treatment with chemotherapy as a novel strategy for effectively targeting metastasis, particularly in a neoadjuvant treatment setting."

Journal • Metastases • Breast Cancer • Oncology • Solid Tumor • EZR • NF-κβ

Ezrin and Its Phosphorylated Thr567 Form Are Key Regulators of Human Extravillous Trophoblast Motility and Invasion. (PubMed, Cells) - "Loss-of-function experiments were carried out in EVT HTR8/SVneo and Swan71, as well as primary cells, using either ezrin siRNAs or the phosphorylation Thr567 inhibitor NSC668394, resulting in significant reductions in both cell motility and cellular invasion, albeit with differences between the cells used. Our analysis further demonstrated that an increase in focal adhesion was, in part, able to explain some of the molecular mechanisms involved. Data collected using human placental sections and protein lysates further showed that ezrin expression was significantly higher during the early stage of placentation and, importantly, clearly seen in the EVT anchoring columns, further supporting the potential role of ezrin in regulating migration and invasion in vivo."

Journal • Oncology • Solid Tumor • EZR

Patient derived gliomaspheres exhibit HA concentration dependent invasiveness in 3D hydrogels (AACR 2022) - "Moreover, inhibition of the CD44-Ezrin-Actin axis, using NSC668394, reduced migratory activity in hydrogels with higher HA (>0.25% w/v), while slightly increasing invasion in hydrogels with low HA (0.10 w/v%). In sum, results demonstrate the use of a matrix-mimetic, 3D hydrogel system in which to study GBM invasion through the local extracellular matrix."

Clinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CD44 • EZR

[VIRTUAL] PHARMACOLOGICAL INHIBITION OF EZRIN REDUCES GROWTH AND REGULATES APOPTOSIS AND CELL CYCLE RELATED GENES IN ACUTE LYMPHOBLASTIC LEUKEMIA (HEMO 2021) - "Objectives Acute lymphoblastic leukemia (ALL) is a hematologic neoplasm characterized by an arrest in the process of differentiation of lymphoid precursors at an early stage and which can invade bone marrow, peripheral blood and extramedullary sites. The therapeutic options available to adult patients remain limited, and the 5-year overall survival rate is less than 45%. One of the main goals of treatment is to prevent relapses and reduce invasiveness in other organs. Recently, our research group identified the EZR gene, which encodes the ezrin protein, as an independent prognostic marker and molecular target for acute myeloid leukemia. Ezrin is an important cytoskeleton-associated protein that allows signal transduction between membrane proteins and actin filaments. The aim of the present study was to verify the impact of pharmacological inhibition of ezrin on viability, autonomous clonal growth and gene expression in ALL cell models.Material..."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BAX • BCL2 • BCL2L1 • CCNA2 • CCNB1 • CDKN1A • CDKN1B • EBF1 • ETV6 • EZR • MCL1 • PTEN • RUNX1

[VIRTUAL] AZATHIOPRINE IMPAIRS PANCREATIC DUCTAL CHLORIDE AND BICARBONATE SECRETION BY DISRUPTING CFTR PLASMA MEMBRANE RETENTION IN MICE (UEGW 2021) - "In vivo fluid-secretion was measured in ketamine-xylazine sedation, then pancreatic ductal segments (PD), pancreatic ductal organoids (OCs), or acinar cells were isolated...Changes in intracellular pH-, and Cl- levels were determined using ratio microfluorimetry both in the presence and absence of CFTR, ezrin, and Rac1 inhibitors (Inh-172, NSC668394, and Ehop-016, respectively)... AZA can impair ductal Cl- and HCO3--secretion by disrupting CFTR plasma membrane tethering in mice, however, it does not change neither the acinar cell viability, nor the severity of experimental pancreatitis. Our results suggesting that AZA can increase the frequency rather than the severity of AP are in accordance with the clinical experience. To fully understand the pathomechanism of TIP, further experiments on both pancreatic ducts and acini are needed."

Preclinical • Anesthesia • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immune Modulation • Immunology • Inflammation • Pancreatitis • Pediatrics • Pulmonary Disease • Respiratory Diseases • CFTR • EZR

Comprehensive analysis of cytoskeleton regulatory genes identifies ezrin as a prognostic marker and molecular target in acute myeloid leukemia. (PubMed, Cell Oncol (Dordr)) - "From our data we conclude that EZR expression may serve as a prognostic factor in AML. Our preclinical findings indicate that ezrin inhibitors may be employed as a putative novel class of AML targeting drugs."

Biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • EIF4EBP1 • EZR

CD8 T cells actively penetrate into hepatocytes via CD44/p-ERM/F-actin pathway in autoimmune hepatitis. (PubMed, J Dig Dis) - "CD8+ T cells penetrated into hepatocytes actively via CD44/p-ERM/F-actin signaling pathway and undergo apoptosis, may be a compensative mechanism to attenuate overwhelming immune attack in AIH."

Journal • Hepatology • Immunology • CD44 • CD8 • EZR