NSC305787

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.

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.

The present findings provide promising evidence that ezrin may be a molecular target in the treatment of cervical and gastric carcinoma.

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.

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.

Our study provides insights into EZR as a pharmacological target in CLL, shedding light on a novel strategy for treating this disease.

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 and Methods A Jurkat (mutated PTEN) NALM6 (ETV6-EBF1) and REH leukemic cell lines (ETV6-RUNX1) were treated with increasing concentrations of the ezrine inhibitors, NSC305787 and NSC668394. Cell viability was evaluated by the MTT assay, the growth of autonomous colonies by cultivation in methylcellulose in the absence of growth factors, gene expression analyzes were performed by quantitative PCR to evaluate the expression of genes related to cell cycle and apoptosis. Statistical analyzes were performed by ANOVA test and Bonferroni post-test and a p value < 0.05 was considered statistically significant.Results Treatment with both inhibitors was able to significantly reduce cell viability of Jurkat, NALM6 and REH cells in a concentration-dependent manner (p < 0.05). Compound NSC305787 had greater potency and efficacy than NSC668394, so compound NSC305787 was selected for further studies. IC50 values ​​for compound NSC305787 were 5.1 µM for Jurkat, 3.3 µM for NALM6 and 4.3 µM for REH at the 24-hour treatment time. Long-term treatment with NSC305787 reduced the autonomous clonal growth of Jurkat, NALM6 and REH cells in a concentration-dependent manner (p < 0.05). A panel of 12 genes related to cell cycle and apoptosis was investigated by quantitative RT-PCR. NSC305787 (1.6 μM for 24 hours), down-regulated CCNA2, and up-regulated CDKN1A, BCL2L1 and BIM (p < 0.05) in Jurkat cells; down-regulated CCNA2 and BCL2, and up-regulated BCL2L1, BAX and BAD in NALM6 cells; down-regulated CCNA2 and CCNB1 and up-regulated CDKN1A, CDKN1B, BCL2L1, MCL1 and BAX in REH cells.Discussion The downregulation of genes related to cell cycle progression (CCNA2 and CCNB1) and anti-apoptotic response (BCL2) and upregulation of related genes cell cycle arrest (CDKN1A, CDKN1B), pro-apoptotic genes (BAX) support the hypothesis that NSC305787 is involved in cell death induction mechanisms.Conclusion Our Results indicate that the ezrin inhibitor, NSC305787, has antileukemic effects in ALL , including reduced viability and clonogenicity. Support: CNPq, CAPES and FAPESP.

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.