Delving into the Latest Updates on TH5487 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

OGG1

Mechanism

OGG1 inhibitors(8-oxoguanine DNA glycosylase inhibitors)

Therapeutic Areas

Other Diseases

Active Indication

Inflammation

Inactive Indication-

Originator Organization

Karolinska Institutet

Active Organization

Karolinska Institutet

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC19H18BrIN4O2

InChIKeyFZLKVWWPFOLPKF-UHFFFAOYSA-N

CAS Registry2304947-71-3

AbstractReactive oxygen species (ROS)‐induced oxidative DNA damages have been considered the main cause of mutations in genes, which are highly related to carcinogenesis and tumour progression. Extracellular vesicles play an important role in cancer metastasis. However, the precise role of DNA oxidative damage in extracellular vesicles (EVs)‐mediated cancer cell migration and invasion remains unclear. Here, we reveal that ROS‐mediated DNA oxidative damage signalling promotes tumour metastasis through increasing EVs release. Mechanistically, 8‐oxoguanine DNA glycosylase (OGG1) recognises and binds to its substrate 8‐oxo‐7,8‐dihydroguanine (8‐oxoG), recruiting NF‐κB to the synaptotagmin 7 (SYT7) promoter and thereby triggering SYT7 transcription. The upregulation of SYT7 expression leads to increased release of E‐cadherin‐loaded EVs, which depletes intracellular E‐cadherin, thereby inducing epithelial‐mesenchymal transition (EMT). Notably, Th5487, the inhibitor of DNA binding activity of OGG1, blocks the recognition and transmission of oxidative signals, alleviates SYT7 expression and suppresses EVs release, thereby preventing tumour progression in vitro and in vivo. Collectively, our study illuminates the significance of 8‐oxoG/OGG1/SYT7 axis‐driven EVs release in oxidative stress‐induced tumour metastasis. These findings provide a deeper understanding of the molecular basis of cancer progression and offer potential avenues for therapeutic intervention.

100 Deals associated with TH5487

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