Delving into the Latest Updates on GF-109203X with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

GF 109203X, GF109203X

Target

GRK6 x PKC

Action

antagonists, inhibitors

Mechanism

GRK6 antagonists(G protein-coupled receptor kinase 6 antagonists), PKC inhibitors(Protein kinase C inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesSkin and Musculoskeletal Diseases+ [1]

Active Indication-

Inactive Indication

InflammationNeoplasmsRheumatic Diseases

Originator Organization

Pfizer Inc.

Active Organization-

Inactive Organization

Pfizer Inc.

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC25H24N4O2

InChIKeyQMGUOJYZJKLOLH-UHFFFAOYSA-N

CAS Registry133052-90-1

Long-term depression (LTD), a form of synaptic plasticity, is impaired in the nucleus accumbens (NAc) in depression. While TRPV4 activation regulates synaptic transmission in the hippocampus, its effects in the NAc remain unclear. Here, we examined the effects of TRPV4 activation on LTD induction in the NAc and depressive-like behavior. Mice that were administered the TRPV4 agonist GSK1016790A into the NAc (GSK-mice) showed depressive-like behavior and impaired LTD induction in NAc slices. Additionally, the mRNA and protein levels of dopamine D2 receptor (D2R) and A-type gamma-aminobutyric acid receptor (GABA_AR) were markedly decreased in the NAc of GSK-mice. Meanwhile, administering a D2R (quinpirole) or GABA_AR (muscimol) agonist reversed LTD impairment in the NAc. The protein levels of phosphorylated protein kinase C (p-PKC) increased markedly and that of phosphorylated protein kinase B (p-Akt) decreased in the NAc of GSK mice. Administration of a PKC antagonist (GF109203X) or phosphatidylinositol 3-kinase (PI3K) agonist (740 Y-P) significantly increased GABA_AR protein levels and restored LTD induction in the NAc of GSK-mice. Administration of quinpirole increased p-Akt and GABA_AR protein levels in the NAc of GSK-mice. Finally, administration of quinpirole, muscimol, GF109203X or 740 Y-P improved the depressive-like behavior in GSK-mice. This study suggests that activation of TRPV4 impairs LTD induction in the NAc and induces depressive-like behavior, which is likely mediated by down-regulating D2R to inhibit PI3K-Akt pathway, and activating PKC to decrease the expression of GABA_AR.

01 Feb 2025·FUNDAMENTAL & CLINICAL PHARMACOLOGY

Induction of Ca²⁺ signaling and cytotoxic responses of human lung fibroblasts upon an antihistamine drug oxatomide treatment and evaluating the protective effects of Ca²⁺ chelating

Article

Author: Sun, Gwo‐Ching ; Yang, Zong‐Da ; Hsieh, Kai‐Wei ; Liang, Wei‐Zhe

Abstract:

Background:

Oxatomide, an antihistamine drug of the diphenylmethylpiperazine family, has anti‐inflammatory effects in airway disease. Because oxatomide was shown to cause diverse physiological responses in several cell models, the impact of oxatomide on Ca2+ signaling and its related physiological effects has not been explored in IMR‐90 human fetal lung fibroblasts.

Objectives:

This study assessed the effect of oxatomide on cell viability and intracellular free Ca2+ concentrations ([Ca2+]i) and examined whether oxatomide‐induced cytotoxicity through Ca2+ signaling in IMR‐90 cells.

Methods:

Cell viability was measured by the cell proliferation reagent (WST‐1). [Ca2+]i was measured by the Ca2+‐sensitive fluorescent dye fura‐2.

Results:

Oxatomide (10–40 μM) concentration dependently reduced cell viability and induced [Ca2+]i rises in IMR‐90 cells. This cytotoxic effect was reversed by chelation of cytosolic Ca2+ with BAPTA‐AM. In terms of Ca2+ signaling, oxatomide‐caused Ca2+ entry was inhibited by modulators of store‐operated Ca2+ channels (2‐APB and SKF96365) and protein kinase C (PKC) inhibitor (GF109203X). Furthermore, oxatomide‐induced Ca2+ influx was confirmed by Mn2+‐induced quench of fura‐2 fluorescence. In a Ca2+‐free medium, preincubation with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin inhibited oxatomide‐evoked [Ca2+]i rises. Conversely, treatment with oxatomide abolished thapsigargin‐induced [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 also inhibited oxatomide‐caused [Ca2+]i rises.

Conclusion:

In IMR‐90 cells, oxatomide‐induced cytotoxicity by preceding [Ca2+]i rises involving PKC‐sensitive store‐operated Ca2+ entry and PLC‐dependent Ca2+ release from the endoplasmic reticulum. BAPTA‐AM, with its Ca2+ chelating effects, may be a potential compound for preventing oxatomide‐induced cytotoxicity.

01 Jan 2025·EUROPEAN JOURNAL OF PHARMACOLOGY

Modified lipoprotein-induced sFlt1 production in human placental trophoblasts is mediated by protein kinase C

Article

Author: Yu, Jeremy Y. ; Curtis, Tim M ; Yu, Jeremy Y ; Lyons, Timothy J ; Curtis, Tim M. ; Li, Yanchun ; Zhao, Jiawu ; Chow, Rebecca P ; Lyons, Timothy J. ; Chow, Rebecca P.

BACKGROUND:

Preeclampsia is prevalent in women with diabetes, but the mechanism is unclear. We previously found that oxidized, glycated lipoproteins robustly upregulated soluble fms-like tyrosine kinase-1 (sFlt1), a key mediator of preeclampsia. Here, we determined the role of protein kinase C (PKC) and its subtypes in sFlt1 regulation in placental trophoblasts, and whether this mechanism might mediate the effect of modified lipoproteins.

METHODS:

Cultured human HTR8/SVneo and BeWo trophoblasts were treated with the PKC activator phorbol-12-myristate-13-acetate (PMA) for 24h, ± PKC inhibitors GF109203X (general), Ro31-8220 (PKCα-selective), LY333531 (PKCβ-selective) and rottlerin (PKCδ-selective). The effect of 'heavily oxidized, glycated' low-density lipoproteins (HOG-LDL) vs. native LDL (N-LDL), ± high glucose (30 mM), was evaluated in HTR8/SVneo cells. sFlt1 secretion (ELISA), mRNA expression (RT-qPCR), and cellular PKC activity were measured.

RESULTS:

PMA stimulated robust sFlt1 release and mRNA expression in both cell lines; these effects were inhibited by GF109203X, Ro31-8220 and LY333531 in a concentration-dependent manner. Rottlerin inhibited sFlt1 in BeWo, but modestly enhanced it in HTR8/SVneo cells. HOG-LDL enhanced PKC activity vs. N-LDL in HTR8/SVneo cells. Also, HOG-LDL, but not high glucose, significantly increased sFlt1 secretion and mRNA expression; this response was inhibited by GF109203X, Ro31-8220 and LY333531 at concentrations comparable to those that blocked PMA induction of sFlt1.

CONCLUSION:

Modified lipoproteins upregulate sFlt1 in trophoblasts via a PKC-mediated mechanism, involving at least α and β isoforms. The data suggest potential therapeutic targets to reduce the risk of preeclampsia in women with diabetes.

100 Deals associated with GF-109203X

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