Delving into the Latest Updates on Nefextinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [7]

Target

FGFRs x FLT3 x HPK1 x JAK x PDGFR x VEGFR

Action

antagonists, inhibitors

Mechanism

FGFRs antagonists(Fibroblast growth factor receptors antagonists), FLT3 inhibitors(Tyrosine-protein kinase receptor FLT3 inhibitors), HPK1 inhibitors(Mitogen-activated protein kinase kinase kinase kinase 1 inhibitors)

+ [3]

Therapeutic Areas

NeoplasmsDigestive System DisordersHemic and Lymphatic Diseases+ [2]

Active Indication

Acute Myeloid LeukemiaAdvanced Malignant Solid NeoplasmExtensive stage Small Cell Lung Cancer+ [7]

Inactive Indication

Advanced Colorectal AdenocarcinomaAdvanced Gastric AdenocarcinomaGastrooesophageal junction cancer+ [1]

Originator Organization

Guangzhou Zaiji Medical Technology Co., Ltd.

Active Organization

Guangzhou Zaiji Medical Technology Co., Ltd.Maxinovel Pty., Ltd.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

RegulationSpecial Review Project (China), Orphan Drug (United States)

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Structure/Sequence

Molecular FormulaC22H23FN6OS

InChIKeyAVIOBQFPAGEICQ-UHFFFAOYSA-N

CAS Registry2070931-57-4

Background: Endothelial-to-mesenchymal transition (EndMT) is a cellular reprogramming mechanism by which endothelial cells acquire a mesenchymal phenotype. Endothelial cell dysfunction is the initiating factor of atherosclerosis (AS). Increasing evidence suggests that EndMT contributes to the occurrence and progression of atherosclerotic lesions and plaque instability. However, the mechanisms leading to EndMT in atherosclerotic plaques' microenvironment are poorly understood. Methods: Single-cell sequencing data of atherosclerotic plaques in mice fed with high-fat diet for different time periods were analyzed. Using quantitative polymerase chain reaction, western blotting, and immunohistochemistry, we demonstrated that the expression of PIM1 in ox-LDL stimulated endothelial cells and in human and mouse atherosclerotic lesions. ApoE ^-/- C57 mice were injected recombinant adeno-associated virus serotype 9 through tail vein to explore the role of PIM1 in atherosclerosis. Co-immunoprecipitation (Co-IP) was used to verify the substrates of PIM1. Hematoxylin and eosin (H&E) staining, Oil Red O staining, and Masson's trichrome staining were used to assess the size of atherosclerotic plaques, lipid content, and collagen fiber content, respectively. Results: PIM1 expression in endothelial cells increased with the progression of AS in vivo. Endothelial cell-specific PIM1 knockdown negatively regulated atherosclerosis progression and the EndMT process. Knockdown of PIM1 in endothelial cells in vitro attenuated ox-LDL-induced EndMT. This process was primarily due to the reduction of PIM1, which led to decreased phosphorylation of NDRG1 at Ser330, and subsequently, reduced NDRG1 nuclear translocation. Consequently, the interaction between NDRG1 and PTBP1 was affected, ultimately impacting the mRNA levels of Vimentin, ZEB1, Slug, Snail, N-Cadherin, TAGLN, and α-SMA. The small molecule Max-40279 could inhibit NDRG1 phosphorylation at Ser330 and suppress EndMT. Conclusion: Our findings revealed the PIM1/P-NDRG1(S330)/PTBP1/EndMT axis as a critical factor promoting AS progression and could generate new strategies to prevent AS.

100 Deals associated with Nefextinib

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15191

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 2	China	Guangzhou Zaiji Medical Technology Co., Ltd.	25 Jul 2022
Advanced gastric carcinoma	Phase 2	China	Guangzhou Zaiji Medical Technology Co., Ltd.	25 Jun 2022
Colorectal Cancer	Phase 2	China	Guangzhou Zaiji Medical Technology Co., Ltd.	29 Nov 2021
Myelodysplastic Syndromes	Phase 2	China	Guangzhou Zaiji Medical Technology Co., Ltd.	09 Sep 2021
Refractory acute myeloid leukemia	Phase 2	China	Guangzhou Zaiji Medical Technology Co., Ltd.	09 Sep 2021
Relapsing acute myeloid leukemia	Phase 2	China	Guangzhou Zaiji Medical Technology Co., Ltd.	09 Sep 2021
Advanced Gastric Adenocarcinoma	Preclinical	China	Maxinovel Pty., Ltd.	01 Jun 2022
Gastrooesophageal junction cancer	Preclinical	China	Maxinovel Pty., Ltd.	01 Jun 2022
Advanced Colorectal Adenocarcinoma	Preclinical	China	Maxinovel Pty., Ltd.	31 Jan 2022
Metastatic Colorectal Carcinoma	Preclinical	China	Maxinovel Pty., Ltd.	31 Jan 2022

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


Company_Website Manual	Phase 1	Acute Myeloid Leukemia FLT3野生型	-	MAX-40279+阿扎胞苷	(chowttgqum) = tozlwwukvr aijbsmbzqb (iqozapdclw ) View more	Positive	01 Oct 2023