Delving into the Latest Updates on SR-1001 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

SR 1001, SR1001

Target

RORα x RORγt

Action

inhibitors

Mechanism

RORα inhibitors(RAR related orphan receptor A inhibitors), RORγt inhibitors(RAR-related orphan receptor gamma 2 inhibitors)

Therapeutic Areas

Immune System Diseases

Active Indication-

Inactive Indication

Autoimmune Diseases

Originator Organization

The Scripps Research Institute

Active Organization-

Inactive Organization

The Scripps Research Institute

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC15H13F6N3O4S2

InChIKeyOZBSSKGBKHOLGA-UHFFFAOYSA-N

CAS Registry1335106-03-0

Glycolysis-related microglial polarization contributes to the migraine (CM), which are closely associated with the PKM2-STAT3/NF-κB axis. Viticis Fructus has been historically prescribed in Traditional Chinese Medicine for alleviating CM, casticin as the active compound of Viticis Fructus has the therapeutic potential for CM.

AIM OF THE STUDY:

To investigate the mechanism of casticin in treating CM, highlighting the role of PKM2-STAT3/NF-κB axis in mediating microglial polarization and glycolysis.

MATERIALS AND METHODS:

The recurrent nitroglycerin (NTG) injections were used to establish CM rat models, then nociceptive thresholds, migraine-like symptoms, blood-brain barrier (BBB) integrity, the IL-17 levels and other inflammatory mediators, glycolysis, and the PKM2-STAT3/NF-κB axis were assessments. Next, IL-17A-treated BV-2 cells were used to demonstrate the effects of casticin on microglial polarization, glycolysis, and the PKM2-STAT3/NF-κB axis. Last, the SR1001 and brodalumab were used in NTG-injected rats and IL-17A-stimulated BV2 cells for reverse verification.

RESULTS:

Casticin reduced IL-17 entry into the TNC, suppressed inflammatory mediator release, decreased CGRP levels, inhibited microglial inflammatory polarization, reduced the level of glycolysis. Moreover, casticin markedly inhibited the PKM2-STAT3/NF-κB axis in the TNC, which jointly validated by WB and immunofluorescence colocalization. Additionally, SR1001 and brodalumab reversed the effects of Casticin in vivo and in vitro, which was mainly accomplished via PKM2-dependent microglial polarization.

CONCLUSIONS:

Casticin alleviated pain sensitization and CM-like symptoms in CM rats by targeting IL-17-mediated microglial polarization and glycolysis via inhibition of the PKM2-STAT3/NF-κB axis, which explains the mechanism by which casticin relieves CM.

01 May 2025·INTERNATIONAL IMMUNOPHARMACOLOGY

IL-17 enhanced the susceptibility to fluoxetine resistance in depression via the JAK1-STAT6 signaling pathway

Article

Author: Zhang, Mingjia ; Huang, Xueru ; Liu, YueYing ; Yang, Qingqing ; Qu, Yuanguo ; Zhang, Xin ; Zhu, Aisong ; Yu, Wumin ; Shen, Yineng ; Hong, Yaonan ; Ao, Haiqing ; Jia, Ruiting ; Huang, Yike ; Zhang, Yi ; Pang, Zixin ; Gao, Xing ; Cai, Ziling

AIMS:

This study aims to investigate the role of IL-17 in fluoxetine resistance in depression.

METHODS:

The Weighted Gene Coexpression Network Analysis (WGCNA) was utilized to analyze differentially expressed genes between response to antidepressant (GRA) group and the resistance to antidepressant (AR) group. Furthermore, a treatment resistance model of depression was established in Chronic unpredictable mild stress (CUMS) mice administrated with fluoxetine (widely used clinical medication for the treatment of depression) according to sucrose preference rate. Depression-like behaviors in mice were detected in Control group, CUMS group, GRA group, AR group, and SR1001 (Th17 differentiation inhibitor) group. Subsequently, HT22 cells were exposed to IL-17 secreted by Th17 differentiation. Transcriptome sequencing from the Control and IL-17 group was used to screen differential genes. HT22 cells were then transfected with si-JAK1 or si-STAT6. Th17 differentiation, the integrity of the blood-brain barrier (BBB), JAK1-STAT6 signaling pathway related proteins were detected by western blot, immunocytochemistry, flow cytometric analysis, ELISA experiments, immunofluorescence, and PCR.

RESULT:

The WGCNA showed that Th17 differentiation played an important role in the treatment resistance of depression. The results of the following animal experiments showed that fluoxetine resistance resulted in a reduction in total distance and average speed in the Open Field Test (OFT), an increase in immobility time during the Forced Swim Test (FST) and Tail Suspension Test (TST). It also regulated the expression of the SERT protein, Th17 differentiation, IL-17 secretion, and compromised the integrity of BBB, yielding similar outcomes in CUMS mice. However, these results could be reversed by SR1001. Moreover, IL-17 effectively elevated the SERT protein level and activated the JAK1-STAT6 signaling pathway in vivo and in vitro.

CONCLUSION:

The inhibition of Th17 differentiation and the reduction of peripheral IL-17 release could decrease sensitivity to fluoxetine resistance and relieve the depression-like behavior. This process might be associated with the JAK1-STAT6 pathway.

01 May 2025·AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY

The molecular circadian clock of eosinophils: a potential therapeutic target for asthma

Article

Author: Teppan, Julia ; Bärnthaler, Thomas ; Farzi, Aitak ; Böhm, Eva ; Gioan-Tavernier, Gael ; Platt, Hazel ; Durrington, Hannah ; Wolf, Peter ; Heinemann, Akos

Our findings highlight the role of the circadian system as an immunomodulatory regulator, biomarker, and therapeutic target in chronic inflammatory diseases. The observed inflammation-driven downregulation of the molecular circadian clock may also represent a key mechanism that triggers the switch from homeostatic to pro-inflammatory eosinophils. Furthermore, we demonstrate for the first time that pharmacologic inhibition of ROR resets the molecular circadian clock and induces anti-inflammatory and lung-protective effects without disrupting circadian rhythms.

100 Deals associated with SR-1001

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