Delving into the Latest Updates on Ezatiostat Hydrochloride with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Ezatiostat, Ezatiostat HCl, Ezatiostat hydrochloride (USAN)

+ [5]

Target

GSTP1

Mechanism

GSTP1 inhibitors(Glutathione S-transferase Pi inhibitors)

Therapeutic Areas

NeoplasmsCongenital DisordersHemic and Lymphatic Diseases+ [2]

Active Indication-

Inactive Indication

Chemotherapy-Induced Febrile NeutropeniaChromosome 5q Deletion Syndromemetastatic non-small cell lung cancer+ [2]

Originator Organization

Telik, Inc.

Active Organization-

Inactive Organization

Telik, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC27H35N3O6S

InChIKeyGWEJFLVSOGNLSS-WPFOTENUSA-N

CAS Registry168682-53-9

View All Structures (2)

This is an open label, multicenter Phase 1 dose escalation study evaluating five doses of ezatiostat in combination with lenalidomide in patients with non-del(5q) low to intermediate 1 risk MDS. The HI-E, HI-N, HI-P rates [by International Working Group (IWG) 2006 criteria] and safety of each treatment group will be evaluated to select the optimal dose of ezatiostat in combination with lenalidomide for future studies.

Start Date01 Nov 2009

Sponsor / Collaborator

Telik, Inc.

100 Clinical Results associated with Ezatiostat Hydrochloride

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100 Translational Medicine associated with Ezatiostat Hydrochloride

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100 Patents (Medical) associated with Ezatiostat Hydrochloride

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23

Literatures (Medical) associated with Ezatiostat Hydrochloride

01 Nov 2024·Phytomedicine

Galangin alleviated Doxorubicin-induced cardiotoxicity by inhibiting ferroptosis through GSTP1/JNK pathway

Article

Author: Hu, Xiaoshuang ; Shu, Guangjie ; Zhang, Shenshen ; Li, Junyan ; Chen, Ke ; Wang, Jian ; Liu, Bing ; Huang, Huiru ; Chen, Xi ; Lu, Wenxin

BACKGROUNDDoxorubicin (DOX) is a potent anticancer medication, but its significant cardiotoxicity poses a challenge in clinical practice. Galangin (Gal), a flavonoid compound with diverse pharmacological activities, has shown potential in exerting cardioprotective effects. However, the related molecular mechanism has not been fully elucidated.PURPOSECombined with bioinformatics and experimental verification methods to investigate Gal's potential role and underlying mechanisms in mitigating DOX-induced cardiotoxicity (DIC).METHODSC57BL/6 mice received a single dose of DOX via intraperitoneal injection 4 days before the end of the gavage period with Gal. Myocardial injury was evaluated using echocardiography, myocardial injury biomarkers, Sirius Red and H&E staining. H9c2 cells were stimulated with DOX to mimic DIC in vitro. The potential therapeutic target of Gal was identified through network pharmacology, molecular docking and cellular thermal shift assay (CETSA), complemented by an in-depth exploration of the GSTP1/JNK signaling pathway using immunofluorescence. Subsequently, the GSTP1 inhibitor Ezatiostat (Eza) substantiated the signaling pathway.RESULTSGal administration considerably raised DOX-inhibited the left ventricular ejection fractions (LVEF), reduced levels of myocardial injury markers (c-TnI, c-TnT, CKMB, LDH, and AST), and alleviated DOX-induced myocardial histopathological injury and fibrosis in mice, thereby improving cardiac dysfunction. The ferroptosis induced by DOX was inhibited by Gal treatment. Gal remarkably ameliorated the DOX-induced lipid peroxidation, accumulation of iron and Ptgs2 expression both in H9c2 cells and cardiac tissue. Furthermore, Gal effectively rescued the DOX-inhibited crucial regulators of ferroptosis such as Gpx4, Nrf2, Fpn, and Slc7a11. The mechanistic investigations revealed that Glutathione S-transferase P1 (GSTP1) may be a potential target for Gal in attenuating DIC. Gal act on GSTP1 by stimulating its expression, thereby enhancing the interaction between GSTP1 and c-Jun N-terminal kinase (JNK), leading to the deactivation of JNK/c-Jun pathway. Furthermore, interference of GSTP1 with inhibitor Eza abrogated the cardioprotective and anti-ferroptotic effects of Gal, as evidenced by decreased cell viability, reduced expression of GSTP1 and Gpx4, elevated MDA levels, and promoted phosphorylation of JNK and c-Jun compared with Gal treatment.CONCLUSIONGal could inhibit ferroptosis and protect against DIC through regulating the GSTP1/JNK pathway. Our research has identified a novel pathway through which Gal regulates DIC, providing valuable insights into the potential therapeutic efficacy of Gal in mitigating cardiotoxic effects.

01 Mar 2023·Advanced Science

Targeting GSTP1 as Therapeutic Strategy against Lung Adenocarcinoma Stemness and Resistance to Tyrosine Kinase Inhibitors

Article

Author: Chen, Jun‐Jiang ; Lei, Zi‐Ning ; Ruan, Ye Chun ; Xiao, Zhi‐Jie ; Yam, Judy Wai Ping ; Pan, Yihang ; Wong, Maria Pik ; Wang, Si‐Qi ; Jiang, Yuchen

AbstractGlutathione S‐transferase pi (GSTP1), a phase II detoxification enzyme, is known to be overexpressed and mediates chemotherapeutic resistance in lung cancer. However, whether GSTP1 supports cancer stem cells (CSCs) and the underlying mechanisms in lung adenocarcinoma (LUAD) remain largely unknown. This study unveiled that GSTP1 is upregulated in lung CSCs and supports tumor self‐renewal, metastasis, and resistance to targeted tyrosine kinase inhibitors of LUAD both in vitro and in vivo. Mechanistically, CaMK2A (calcium/calmodulin‐dependent protein kinase 2 isoform A)/NRF2 (nuclear factor erythroid 2‐related factor 2)/GSTP1 is uncovered as a regulatory axis under hypoxia. CaMK2A increased GSTP1 expression through phosphorylating the Sersine558 residue of NRF2 and promoting its nuclear translocation, a novel mechanism for NRF2 activation apart from conventional oxidization‐dependent activation. Upregulation of GSTP1 in turn suppressed reactive oxygen species levels and supported CSC phenotypes. Clinically, GSTP1 analyzed by immunohistochemistry is upregulated in a proportion of LUAD and serves as a prognostic marker for survival. Using patient‐derived organoids from an ALK‐translocated LUAD, the therapeutic potential of a specific GSTP1 inhibitor ezatiostat in combination treatment with the ALK inhibitor crizotinib is demonstrated. This study demonstrates GSTP1 to be a promising therapeutic target for long‐term control of LUAD through targeting CSCs.

01 Nov 2021·Redox BiologyQ1 · BIOLOGY

Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2

Q1 · BIOLOGY

ArticleOA

Author: D'Alessandro, Angelo ; Sharafi, Mona ; van der Vliet, Albert ; Reynaert, Niki L ; Louis, Renaud ; Manuel, Allison M ; Poynter, Matthew E ; van der Velden, Jos L ; Dixon, Anne E ; ZounematKermani, Nazanin ; Henderson, Colin J ; Wouters, Emiel F ; MacPherson, Maximilian ; Wolf, C Roland ; Qian, Xi ; Adcock, Ian M ; Li, Jianing ; Bohrnsen, Eric ; Erickson, Cuixia ; Aboushousha, Reem ; Chan, Garrett ; van de Wetering, Cheryl ; Janssen-Heininger, Yvonne M ; Irvin, Charles G ; Schleich, Florence ; Lundblad, Lennart K A

BACKGROUNDInterleukin-1-dependent increases in glycolysis promote allergic airways disease in mice and disruption of pyruvate kinase M2 (PKM2) activity is critical herein. Glutathione-S-transferase P (GSTP) has been implicated in asthma pathogenesis and regulates the oxidation state of proteins via S-glutathionylation. We addressed whether GSTP-dependent S-glutathionylation promotes allergic airways disease by promoting glycolytic reprogramming and whether it involves the disruption of PKM2.METHODSWe used house dust mite (HDM) or interleukin-1β in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1β and the selective GSTP inhibitor, TLK199. GSTP and PKM2 were evaluated in sputum samples of asthmatics and healthy controls and incorporated analysis of the U-BIOPRED severe asthma cohort database.RESULTSAblation of Gstp decreased total S-glutathionylation and attenuated HDM-induced allergic airways disease and interleukin-1β-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin-1β-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. ¹³C-glucose metabolomics showed decreased glycolysis flux at the pyruvate kinase step in response to TLK199. GSTP and PKM2 levels were increased in BAL of HDM-exposed mice as well as in sputum of asthmatics compared to controls. Sputum proteomics and transcriptomics revealed strong correlations between GSTP, PKM2, and the glycolysis pathway in asthma.CONCLUSIONSGSTP contributes to the pathogenesis of allergic airways disease in association with enhanced glycolysis and oxidative disruption of PKM2. Our findings also suggest a PKM2-GSTP-glycolysis signature in asthma that is associated with severe disease.

100 Deals associated with Ezatiostat Hydrochloride

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External Link

KEGG	Wiki	ATC	Drug Bank
D08917	-	-	DB05460

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Chromosome 5q Deletion Syndrome	Phase 2	US	Telik, Inc.	01 Oct 2011
Neutropenia, Severe Chronic	Phase 2	US	Telik, Inc.	01 Apr 2009
Chemotherapy-Induced Febrile Neutropenia	Phase 2	US	Telik, Inc.	01 Oct 2008
metastatic non-small cell lung cancer	Phase 2	US	Telik, Inc.	01 Oct 2008
Myelodysplastic Syndromes	Phase 2	US	Telik, Inc.	01 May 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01062152 (Pubmed \| J Hematol Oncol)	Phase 1	Myelodysplastic Syndromes	19	Ezatiostat hydrochloride 2000 mg	(zvplmypkll) = anemia due to lenalidomide qrvmtcucdm (wkmfcfgops ) View more	-	30 Apr 2012
				Ezatiostat hydrochloride 2500 mg