Delving into the Latest Updates on SB-505124 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

ALK4 x ALK5 x ALK7

Action

inhibitors

Mechanism

ALK4 inhibitors(activin A receptor type 1B inhibitors), ALK5 inhibitors(Transforming growth factor beta receptor 1 inhibitors), ALK7 inhibitors(activin A receptor type 1C inhibitors)

Therapeutic Areas-

Active Indication-

Inactive Indication-

Originator Organization

GSK Plc

Active Organization

GSK Plc

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Low-grade gliomas (LGG) are known for their slow growth yet retain the potential to progress to more aggressive malignancies. Glioma cells are frequently exposed to stressors such as hypoxia, nutrient deprivation, and oxidative stress, which disrupt protein folding within the endoplasmic reticulum (ER), leading to ER stress and activation of the unfolded protein response (UPR). ER stress plays a complex role in glioma initiation, progression, and resistance to chemotherapy. Dysregulated signaling between mitochondria and the ER can further exacerbate ER stress, impacting glioma cell survival and proliferation. Elucidating the molecular mechanisms by which mitochondrial interactions influence ER stress may reveal novel therapeutic targets for LGG treatment.

METHODS:

ER-stress related mitochondrial protein-coding genes (ERSMGs) linked to LGG prognosis were identified using Mitocarta3.0, Genecards, CGGA, and TCGA data. A prognostic model was developed via univariate and LASSO-Cox regression and validated by ROC curves. OMA1's role was assessed through knockdown experiments in LGG cell lines.

RESULTS:

Eleven ERSMGs were significantly associated with LGG prognosis. The model achieved reliable predictive accuracy (AUC > 0.6) and stratified patients into high- and low-risk groups with distinct survival rates. High-risk patients exhibited increased sensitivity to SB505124. OMA1 knockdown in LGG cells induced ER stress by promoting mitochondrial fusion, increasing mtROS, ultimately inhibiting cell proliferation and invasion.

CONCLUSION:

This study provides a novel prognostic model based on ERSMGs, offering novel insights into LGG progression and invasion. OMA1-mediated mitochondrial dysfunction and ER stress play critical roles in glioma cell growth and survival, representing potential therapeutic targets.

01 Mar 2025·Biochemistry and Biophysics Reports

An integrated machine learning framework for developing and validating a prognostic risk model of gastric cancer based on endoplasmic reticulum stress-associated genes

Article

Author: Liu, Lei ; Wei, Gang ; Wang, Yan ; Liu, Ru

Background:

Gastric cancer (GC), a prevalent and deadly malignancy, demonstrates poor survival outcomes. Evidence has emerged indicating that disruptions in endoplasmic reticulum homeostasis are significantly implicated in the onset and progression of various oncological conditions. This study was designed to construct a prognostic model based on genes related to endoplasmic reticulum stress(ERS) to predict survival outcomes in patients with GC.

Methods:

Expression profiling data for GC samples were extracted and analyzed from TCGA-STAD, revealing 214 genes related to endoplasmic reticulum stress that show differential expression when compared with normal gastric tissue. Building on these insights, a prognostic model was formulated using data from TCGA-STAD and validated through subsequent analyses of GEO datasets. The tumor immune dysfunction and exclusion(TIDE) algorithm was applied to determine the susceptibility of individuals in high- and low-risk categories to immunotherapy. The presence of immune and stromal cells within the tumor microenvironment was assessed with the aid of the ESTIMATE algorithm. Sensitivity variations to prevalent anticancer drugs between the risk groups were evaluated using the Genomics of Drug Sensitivity in Cancer(GDSC) database, and prospective therapeutic agents were confirmed through molecular docking techniques.

Results:

Thirty-one endoplasmic reticulum stress (ERS)-related differentially expressed genes (DEGs) crucial for prognosis in GC were pinpointed. These DEGs were then used to construct a prognostic model and were considered as independent prognostic factors for GC patients. This risk model proved to have a good predictive performance for estimating the overall survival of these patients. The patients placed into the high-risk group showed worse results and lower sensitivity to immunotherapy. Moreover, five specific targeted therapy drugs, namely BMS-754807, Dasatinib, JQ1, AZD8055 and SB505124, produced better results in the treatment of the high-risk group of patients.

Conclusions:

A new molecular prognostic model associated with ERS was established and validated for GC and showed relatively good discriminative and predictive ability. This model greatly expands the collection of weapons in the armoury of prognostic analysis in GC.

01 Nov 2024·Acta Crystallographica Section F-Structural Biology Communications

Human transforming growth factor β type I receptor in complex with kinase inhibitor SB505124

Article

Author: Rodriguez Buitrago, Jhon A ; Wolf-Watz, Magnus ; Landström, Maréne

The crystal structure of the intracellular domain of transforming growth factor β type I receptor (TβR1) in complex with the competitive inhibitor SB505124 is presented. The study provides insights into the structure and function of TβR1 in complex with SB505124, and as such offers molecular-level understanding of the inhibition of this critical signalling pathway. The potential of SB505124 as an avenue for therapy in cancer treatment is discussed on basis of the results.

100 Deals associated with SB-505124

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