Delving into the Latest Updates on NXC-736 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

NXC-736 - NextGen Bioscience

Target

S1PRs

Action

antagonists

Mechanism

S1PRs antagonists(Sphingosine 1-phosphate receptors antagonists)

Therapeutic Areas

Immune System DiseasesSkin and Musculoskeletal Diseases

Active Indication

Alopecia Areata

Inactive Indication-

Originator Organization

Nextgen Bioscience Co., Ltd.

Active Organization

Nextgen Bioscience Co., Ltd.

Inactive Organization-

License Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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INTRODUCTIONThe functions of S1P receptors have been revealed using genetic and pharmacological tools, including the potent non-selective modulator FTY720. However, studies on subtype-specific agonists and antagonists are limited; hence, the role of S1P₄ remains unclear.OBJECTIVESTo identify a novel function of S1P₄ as a pathogenic factor in stroke using a newly developed S1P₄-selective modulator and S1P₄ knockdown.METHODSHeteroaromatic analogs of FTY720 were synthesized, a β-arrestin assay was conducted against S1P receptors, and the developed compound (NXC736) was characterized as a functional S1P₄ antagonist. To clarify the function of S1P₄, the therapeutic potential of NXC736 in ischemic stroke was determined using a transient middle cerebral artery occlusion (tMCAO) mouse model, which was validated using S1P₄ knockdown. The S1P₄-dependent pathogenic mechanisms were determined using immunohistochemical and biochemical analyses.RESULTSMolecular modeling studies provide valuable clues for understanding S1P₄ selectivity of NXC736. NXC736 contains a triazole ring instead of a phenyl ring and exhibits S1P₄-selective activity as a functional antagonist. Its action on S1P₄ does not require phosphorylation by sphingosine kinase 2. Notably, NXC736 exhibited substantial therapeutic activity against ischemic stroke by attenuating tMCAO-induced acute brain injuries, including brain infarction, neurological deficits, and neuronal apoptosis. This suggested that S1P₄ is a pathogenic factor in ischemic stroke. This function was confirmed using AAV-based S1P₄ knockdown. NXC736 or S1P₄ knockdown attenuated blood-brain barrier disruption, neutrophil infiltration, microglial activation and proliferation, and the upregulation of pro-inflammatory cytokines, thereby demonstrating that S1P₄ influences neuroinflammatory responses in ischemic stroke. The underlying mechanisms were activation of NLRP3 inflammasome, NF-κB, and MAPKs. S1P₄ also contributed to chronic brain injuries caused by ischemic stroke because NXC736 exerted long-term neuroprotective effects against tMCAO challenge.CONCLUSIONUsing a functional S1P₄ antagonist (NXC736) and a genetic tool for S1P₄ knockdown, we identified S1P₄ as a novel pathogenic factor in ischemic stroke.

International Journal of Molecular Sciences

NXC736 Attenuates Radiation-Induced Lung Fibrosis via Regulating NLRP3/IL-1β Signaling Pathway

Article

Author: Lee, Jae Hee ; Jo, Hai In ; Kim, Sang Yeon ; Choi, Hojung ; Cho, Jaeho ; Song, Hyo Jeong ; Cui, Ronglan ; Lee, Bong Yong ; Farh, Mohamed El-Agamy ; Lee, Yoon-Jin ; Lee, Hajeong ; Lee, Yun-Sil ; Park, Sunjoo

Radiation-induced lung fibrosis (RILF) is a common complication of radiotherapy in lung cancer. However, to date no effective treatment has been developed for this condition. NXC736 is a novel small-molecule compound that inhibits NLRP3, but its effect on RILF is unknown. NLRP3 activation is an important trigger for the development of RILF. Thus, we aimed to evaluate the therapeutic effect of NXC736 on lung fibrosis inhibition using a RILF animal model and to elucidate its molecular signaling pathway. The left lungs of mice were irradiated with a single dose of 75 Gy. We observed that NXC736 treatment inhibited collagen deposition and inflammatory cell infiltration in irradiated mouse lung tissues. The damaged lung volume, evaluated by magnetic resonance imaging, was lower in NXC736-treated mice than in irradiated mice. NXC736-treated mice exhibited significant changes in lung function parameters. NXC736 inhibited inflammasome activation by interfering with the NLRP3-ASC-cleaved caspase-1 interaction, thereby reducing the expression of IL-1β and blocking the fibrotic pathway. In addition, NXC736 treatment reduced the expression of epithelial–mesenchymal transition markers such as α-SMA, vimentin, and twist by blocking the Smad 2,3,4 signaling pathway. These data suggested that NXC736 is a potent therapeutic agent against RILF.

100 Deals associated with NXC-736

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