Delving into the Latest Updates on KT-5823 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

KT-5823

Target

Protein kinases

Action

inhibitors

Mechanism

Protein kinases inhibitors

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Neoplasms

Originator Organization

Kyowa Hakko Kogyo Co., Ltd.

Active Organization-

Inactive Organization

Kyowa Hakko Kogyo Co., Ltd.

License Organization-

Drug Highest PhaseDiscontinuedDiscovery

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC29H25N3O5

InChIKeyQTYMDECKVKSGSM-YMUMJAELSA-N

CAS Registry126643-37-6

Nitroglycerin (GTN), a widely used anti-anginal drug, has emerged as a potential alternative therapy for acute ischemic stroke. However, the underlying protective mechanisms of GTN in neuronal ischemic injury remain unclear. This study investigates the neuroprotective effects of GTN on glucose metabolism and endoplasmic reticulum (ER) stress during oxygen-glucose deprivation followed by reoxygenation (OGD/R).

METHODS:

Primary rat cortical neurons were subjected to 2 hours of OGD, followed by either 6 or 24 hours of reoxygenation (OGD/R) or no reoxygenation (OGD only). GTN was administered at reoxygenation onset or at the end of the OGD. The PKG inhibitor KT5823 was administered at the onset of OGD. Cell viability and neuronal apoptosis were assessed using CCK-8 assays, TUNEL staining, and Western blotting. Reactive oxygen species (ROS), lactate, and cyclic guanosine monophosphate (cGMP) levels were measured via ELISA, and nitric oxide (NO) levels were determined using the Griess method. ER stress-related proteins, glycolytic/gluconeogenic enzymes, and signaling molecules were analyzed by qRT-PCR and Western blotting.

RESULTS:

GTN significantly improved neuronal survival, preserved cell integrity, and reduced apoptosis under OGD/R conditions. It restored ROS, lactate, NO, and cGMP levels, but not in the OGD-only group. GTN markedly reduced glycolytic enzymes, gluconeogenic enzymes, and ERS-related proteins. It also enhanced PKG expression while suppressing phosphorylated AMPK, effects observed only under OGD/R conditions. The neuroprotective effects of GTN were abolished by the PKG inhibitor KT5823.

CONCLUSION:

GTN confers neuroprotection in OGD/R injury by activating PKG signaling, alleviating ER stress, and modulating glucose metabolism by suppressing hyperglycolysis and gluconeogenesis.

01 Jun 2025·BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

Silencing RGS7 attenuates atrial fibrillation progression by activating the cGMP-PKG signaling pathway

Article

Author: Huang, Hao ; Zeng, Jie ; Xiong, Yan

BACKGROUND:

Atrial fibrillation (AF) is a common diagnosed heart disease that needs novel managements. This study aimed to seek potential biomarkers and underlying regulatory pathways associated with AF.

METHODS:

Differential expressed genes (DEGs) were identified from the Gene Expression Omnibus database, followed by a protein-protein interaction (PPI) network to discover hub genes. Principal components analysis (PCA) and receiver operating characteristic (ROC) curves were performed to evaluate the ability of hub genes to discriminate between AF and control. RGS7 was selected as a key hub gene, and genes co-expressed with RGS7 were identified for functional enrichment analysis. Further in vivo and in vitro experiments were conducted to investigate the effects of silencing RGS7 on AF and the potential pathway.

RESULTS:

We identified top 5 hub genes (RGS7, EGFR, RGS4, GNA13 and RGS11) from the PPI network. PCA showed these genes could distinguish between AF and control samples, with 100 % of the area under curve (AUC) values. Silencing RGS7 inhibited cell apoptosis, inflammation and oxidative stress, and increased mitochondrial membrane potential in angiotensin II (AngII)-treated HL-1 cells, while overexpression of RGS7 reversed the inhibitory effects of silencing RGS7 on AF. Additionally, silencing RGS7 improved cardiac function and decreased cardiac fibrosis in AF rats. The cGMP-PKG signaling pathway was screened as a potential signal transduction pathway, and silencing RGS7 increased the expression of PKG1, while KT5823 blocked the process.

CONCLUSION:

Silencing RGS7 attenuates AF by activating the cGMP-PKG signaling pathway, which may offer directions for selecting biomarkers and regulatory pathways for AF.

01 May 2025·JOURNAL OF NEUROCHEMISTRY

PKG‐Mediated Phosphorylation of TOP2A Activates HDAC to Drive Photoreceptor Cell Death in rd1 Mouse Inherited Retinal Degeneration

Article

Author: Guo, Chunming ; Hou, Chunjiang ; Chen, Maorong ; Yan, Jie ; Hu, Zhulin ; Dong, Yujie ; Jiao, Kangwei ; Zuo, Wandong ; Peng, Hua ; Li, Yan ; Feng, Xiaoxiao ; Liu, Hai ; Paquet‐Durand, François

ABSTRACT:

Inherited retinal degeneration (IRD) is a debilitating condition characterized by progressive loss of photoreceptor cells. However, the underlying mechanisms remain largely unclear. This study investigated the role of DNA topoisomerase II alpha (TOP2A) and its interplay with protein kinase G (PKG) and histone deacetylase (HDAC) in the rd1 mouse model for IRD. Immunofluorescence and quantitative western blotting analyses were performed to evaluate the expression of TOP2A, PKG1, PKG2, HDAC1, and other related markers. TSC24 and suberoylanilide hydroxamic acid were used to specifically inhibit TOP2A and HDAC, respectively, in organotypic retinal explant cultures derived from wild‐type or rd1 mice. Furthermore, we examined the effect of PKG activity on TOP2A phosphorylation using KT5823. Significant upregulation of TOP2A was observed in the rd1 mouse retina compared with wild‐type controls, especially in the outer nuclear layer. Phosphorylation levels of TOP2A strongly correlated with photoreceptor cell death. Treatment with TSC24 significantly reduced TOP2A‐positive and TUNEL‐positive cells. TOP2A phosphorylation was accompanied by HDAC activation, which was mitigated by TSC24. PKG inhibition by KT5823 reduced TOP2A phosphorylation at specific residues and photoreceptor HDAC activity. Our findings position TOP2A in the PKG‐TOP2A‐HDAC photoreceptor degenerative pathway, offering new potential therapeutic targets for combating IRD‐type diseases.image

100 Deals associated with KT-5823

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