NSC305787 / Georgetown University - LARVOL DELTA

New molecular targets in acute leukemias: cytoskeletal regulatory proteins. (PubMed, Biochem Soc Trans) - "Anti-microtubule agents, such as paclitaxel, eribulin, and cyclopenta[b]indole derivatives have demonstrated the ability to inhibit STMN1 by inducing its phosphorylation at regulatory sites, thereby impairing cell viability and promoting apoptosis...Pharmacological inhibitors like NSC305787 have shown efficacy in reducing cell viability, modulating key pathways such as PI3K (phosphatidylinositol-3-kinase)/AKT (AKT serine-threonine protein)/mTOR (mammalian target of rapamycin), and enhancing the activity of standard chemotherapeutics, thereby supporting their potential use in combination therapies. This review aims to explore the roles of STMN1 and EZR in the pathogenesis of acute leukemias, assessing their potential as therapeutic targets. The goal is to synthesize recent evidence to guide the development of more effective inhibitors, focusing on overcoming therapeutic resistance and tailoring treatments to individual profiles."

Journal • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • EZR • mTOR • STMN1

Renal ischemia/reperfusion injury triggers proximal tubular apoptosis and NHE3 dysfunction via p38MAPK/ezrin signaling pathway. (PubMed, Am J Physiol Renal Physiol) - "In vitro, TKPTS cells (mouse proximal tubular cell line) were subjected to IR by treatment with antimycin A (5 μM) and/or SB203580 (1 μM, p38MAPK inhibitor) or NSC305787 (3.2 μM, ezrin phosphorylation inhibitor) and compared with respective controls...Similarly, in vitro IR caused cell apoptosis, increased p38MAPK activation, induced translocation of ezrin from the membrane to the cytosol, and reduced NHE3 activity. Thus, these findings suggest that in ischemic AKI, tubulointerstitial injury is driven by inflammation and apoptosis, mediated through p38MAPK activation and altered ezrin function, ultimately impairing NHE3 activity and exacerbating cell injury."

Journal • Acute Kidney Injury • Cardiovascular • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • EZR

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

Transcriptomics analysis identified ezrin as a potential druggable target in cervical and gastric cancer cells. (PubMed, Clinics (Sao Paulo)) - "The present findings provide promising evidence that ezrin may be a molecular target in the treatment of cervical and gastric carcinoma."

Journal • Cervical Cancer • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • EZR

Ezrin Contributes to the Damage of Airway Epithelial Barrier Related to Diabetes Mellitus. (PubMed, J Inflamm Res) - "Moreover, a specific inhibitor of ezrin Thr567 phosphorylation (NSC305787) inhibited epithelial barrier formation. These results demonstrate that ezrin expression and activation are associated with airway epithelial damage in diabetes mellitus. These findings provide new insights into the molecular pathogenesis of pulmonary infections in diabetes mellitus and may lead to novel therapeutic interventions for airway epithelial barrier damage."

Journal • Diabetes • Infectious Disease • Metabolic Disorders • Respiratory Diseases • EZR

Inhibition of ezrin phosphorylation by NSC305787 attenuates procaterol-stimulated ciliary beating in airway cilia. (PubMed, Biochem Biophys Res Commun) - "Treatment with NSC305787 for 4 h or more decreased the expression of β2AR in the cell membrane and induced vesicle- or dot-like expression of ezrin and β2AR inside the cell. As a result, inhibition of ezrin phosphorylation by NSC305787 attenuated the effect of procaterol-induced activation of ciliary beating in both frequency and distance indices."

Journal • Infectious Disease • EZR

Ezrin Inhibition Overcomes Acquired Resistance to Vemurafenib in BRAFV600E-Mutated Colon Cancer and Melanoma Cells In Vitro. (PubMed, Int J Mol Sci) - "Ezrin inhibition by NSC305787 increased anti-proliferative and pro-apoptotic effects of vemurafenib in the resistant cells in an additive manner, which was accompanied by downregulation of CD44 expression and inhibition of AKT/c-Myc activities. Importantly, ezrin inhibition potentiated anti-proliferative and pro-apoptotic effects of vemurafenib in the resistant melanoma cells in a synergistic manner. Altogether, our study suggests a role of ezrin in acquired resistance to vemurafenib in colon cancer and melanoma cells carrying the BRAFV600E mutation and supports further pre-clinical and clinical studies to explore the benefits of combined BRAF inhibitors and actin-targeting drugs as a potential therapeutic approach for BRAFV600E-mutated cancers."

Journal • Preclinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Solid Tumor • CD44 • EZR • MYC

PHARMACOLOGICAL EZRIN INHIBITION REDUCES GROWTH, ADHESION, MIGRATION AND REGULATE GENE RELATED TO APOPTOSIS AND CELL CYCLE IN ACUTE LYMPHOBLASTIC LEUKAEMIA (EHA 2023) - "Downregulation of genes related to cell cycle progression (CCNA2 and CCNB1) and anti-apoptotic response (BCL2), and upregulation of genes related to cell cycle arrest (CDKN1A, CDKN1B), pro-apoptotic (BAX) response,support the hypothesis that NSC305787 treatment reduces viability by inducing apoptosis. Our results indicate that the ezrin inhibitor, NSC305787, has antileukemic effects in ALL, including reduction of viability and clonogenicity, anti-invasive effects, and regulation of pathways involved in protein synthesis. Supported by CNPq, CAPES and FAPESP."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CCNA2 • CCNB1 • CDKN1A • CDKN1B • CXCL12 • EBF1 • ETV6 • EZR • MCL1 • PTEN • RUNX1

Ezrin Is a Potential Druggable Target in Chronic Lymphocytic Leukemia (ASH 2022) - "Here, we uncover the expression of EZR in samples from CLL and healthy donors, and the cellular and molecular effects of the NSC305787, a pharmacological EZR inhibitor, in CLL cellular models...Pharmacological EZR inhibitions attenuate various cellular and molecular behaviors associated with high risk in CLL and may present a new class of drugs to expand the treatment repertoire of this disease. Supported by: FAPESP, CNPQ, and CAPES."

Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • ANXA5 • CD19 • EZR

Ezrin is highly expressed and a druggable target in chronic lymphocytic leukemia. (PubMed, Life Sci) - "Our study provides insights into EZR as a pharmacological target in CLL, shedding light on a novel strategy for treating this disease."

Journal • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • EZR • TP53

Overexpression of ezrin is associated with acquired resistance to vemurafenib in BRAFV600E mutated colon cancer cells (EACR 2022) - "Expectedly, treatment of resistant cells with the inhibitor of ezrin (NSC305787) for 72 hours significantly reduced cell viability (IC 50 = 7;82 µM). In addition, mRNA expression analysis of colorectal adenocarcinoma in the TCGA dataset using cBioPortal revealed higher expression of EZR in BRAFV600E mutated CRC in comparison with unaltered group. Conclusion Up-regulation of ezrin is a specific molecular feature of vemurafenib-resistant BRAFV600E mutated colon cancer cells whose pharmacological targeting could provide an opportunity to reverse vemurafenib resistance."

Preclinical • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Solid Tumor • EZR

NSC305787, a pharmacological ezrin inhibitor, exhibits antineoplastic activity in pancreatic cancer cells. (PubMed, Invest New Drugs) - "In conclusion, EZR expression is an independent prognosis marker in pancreatic cancer. Our study identifies a novel molecular axis underlying the antineoplastic activity of NSC305787 and provides insights into the development of therapeutic strategies for pancreatic cancer."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • 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

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