Delving into the Latest Updates on SP-600125 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

SP 600125, SP600125

Target

JNK1 x JNK2 x NQO1

Action

inhibitors

Mechanism

JNK1 inhibitors(c-Jun N-terminal kinase 1 inhibitors), JNK2 inhibitors(c-Jun N-terminal kinase 2 inhibitors), NQO1 inhibitors(Quinone reductase 1 inhibitors)

Therapeutic Areas

Nervous System Diseases

Active Indication

Alzheimer Disease

Inactive Indication

Allograft RejectionAsthmaBrain Ischemia+ [1]

Originator Organization

Signal Research Corp.

Active Organization

Kafrelsheikh University

Inactive Organization

Signal Research Corp.

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Cigarette smoke (CS), a major driver of lung cancer (LC), promotes epithelial-mesenchymal transition (EMT) and stemness resulting in metastasis, therapy resistance, and recurrence, but the precise mechanism is elusive. Building on our earlier identification of Runt related transcription factor-2 (RUNX2) and Galectin-3 (Gal-3) as mediators of CS-induced EMT, in this study, we aimed to identify a potential molecular mechanism and delineate the upstream regulators of RUNX2 using A549 lung adenocarcinoma cells and human small airway epithelial cells (SAECs) cultured at the air-liquid interface (ALI). CSE exposure markedly elevated intracellular reactive oxygen species (ROS), assessed via Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay, and promoted invasive behavior (Boyden chamber assay), spheroid formation, and colony formation, the hallmarks of cancer stemness. Expression analysis via RT-qPCR, immunoblotting, and immunocytochemistry revealed that CSE upregulated EMT and stemness-associated markers, notably via upregulating RUNX2 and Galectin-3, at both transcriptional and translational levels through the involvement of c-Jun N-terminal kinase- Mitogen-Activated Protein Kinase (JNK-MAPK) pathways. A specific pharmacological inhibitor of JNK (SP600125) significantly attenuated CSE-induced RUNX2 and Galectin-3 (Gal-3) expression, and also reversed CSE-driven EMT marker alterations, suppressed transcriptional EMT perturbations, and reduced proinflammatory cytokines, including monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α). In conclusion, this study identifies that ROS/JNK/RUNX2/Gal-3 axis drives CS-induced oncogenic plasticity, suggesting that targeted inhibition of this pathway could be an effective strategy for mitigating CS-related LC progression.

01 Dec 2025·INFLAMMATION RESEARCH

Histamine regulates the activity and the expression of the Na+/H+ exchanger (NHE)3 in human epithelial HK-2 cells

Article

Author: Nardini, Patrizia ; Benetti, Elisa ; Rosa, Arianna Carolina ; Gerbino, Chiara ; Cangemi, Luigi ; Foglietta, Federica ; Corsi, Daniele

Abstract:

Objective and design:

Investigate the potential role of histamine and its receptors on the functional expression of the sodium/hydrogen (Na+/H+) exchanger (NHE)3.

Material:

The human epithelial kidney (HK-2) cells were used as an in vitro model of the renal proximal tubule.

Treatment:

HK-2 cells were exposed to histamine 0–1000 nM alone or in combination with chlorphenamine (10 μM) and JNJ-7777120 (1 μM) for 0–48 h. MAPK involvement was determined using the selective inhibitors SB202190 (p38 MAPK), PD98059 (ERK1/2), and SP600125 (SAPK/JNK).

Methods:

Gene and protein expression were evaluated by qPCR and immunoblotting. The activity of NHE3 was measured by the BCECF-AM-based method.

Results:

Histamine (100 nM) induced a concentration-dependent NHE3 gene transcription with a peak 16 h after the treatment, followed by protein translation at 48 h after. A Consistent increase in NHE3 activity was observed at 48 h, but also at 60 min, when both p38 MAPK and ERK1/2 were phosphorylated. JNJ-7777120 blunted the activation and expression of NHE3. Chlorpheniramine was effective only on NHE3 activity.

Conclusions:

Histamine shows early (within 60 min) and late (48 h) effects on NHE3 expression. The histamine H1 and H4 receptors are shown to contribute to these effects differentially. The findings of this study extends the evidence for a direct contribution of histamine on the renal reabsorptive machinery.

01 Dec 2025·BIOCHEMICAL PHARMACOLOGY

Potentiation of acid-sensing ion channel currents by EGF/EGFR signaling in rat dorsal root ganglion neurons

Article

Author: Liu, Ting-Ting ; Yuan, Huan ; Hu, Wang-Ping ; Sun, Fei ; Li, Xue-Mei ; Qiu, Chun-Yu ; Xu, Zhong-Qing

The epidermal growth factor receptor (EGFR) is located in primary sensory neurons and has been implicated in pain processing. However, its mechanism is still not well understood. The aim of the investigation is to determine whether EGFR signaling affects pain-associated ion channels in nociceptive dorsal root ganglion (DRG) neurons. Herein, we reported that the electrophysiological activity of acid-sensing ion channels (ASICs) was enhanced by epidermal growth factor (EGF) in rat DRG neurons. The application of EGF for 5 min concentration-dependently increased acid-evoked ASIC currents. EGF enhanced the ASIC's maximum responses to acidic stimuli without altering its sensitivity. EGFR did appear to be involved in the EGF-mediated potentiation of ASIC currents, since the potentiation was blocked by the EGFR kinase inhibitor AG556. The EGF-mediated potentiation was ERK-dependent, since the potentiation was prevented by the ERK inhibitor U0126. In contrast, the JNK inhibitor SP600125 and the p38 inhibitor SB202190 had no effect on the EGF-mediated potentiation. Moreover, EGF increased the number of acid-evoked action potentials. Finally, injection of EGF into rat paws exacerbated acid-induced nociceptive behavior in dose-dependent manner. The present results that enhanced functional activity of ASICs by EGF/EGFR signaling provided evidence that EGF/EGFR signaling is a promising target for the treatment of pain caused by tissue acidification.

100 Deals associated with SP-600125

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Preclinical	Egypt	Kafrelsheikh University	07 Oct 2024
Allograft Rejection	Preclinical	United States	Signal Research Corp.	-
Asthma	Preclinical	United States	Signal Research Corp.	-
Brain Ischemia	Preclinical	China	Signal Research Corp.	-
Rheumatoid Arthritis	Preclinical	United States	Signal Research Corp.	-