Delving into the Latest Updates on Avagacestat with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Avagacestat (USAN)

Target

γ-secretase

Action

inhibitors

Mechanism

γ-secretase inhibitors(Gamma-secretase inhibitors)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Alzheimer Disease

Originator Organization

Bristol Myers Squibb Co.

Active Organization-

Inactive Organization

Bristol Myers Squibb Co.

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC20H17ClF4N4O4S

InChIKeyXEAOPVUAMONVLA-QGZVFWFLSA-N

CAS Registry1146699-66-2

BACKGROUND & AIMSAlcohol-associated liver disease (ALD) is a major cause of alcohol-related mortality. Sex is an important variable; however, the mechanism behind sex differences is not yet established.METHODSKdm5b flox/flox Kdm5c flox male mice were subjected to gonadectomy or sham surgery. Mice were fed a Western diet and 20% alcohol in the drinking water for 18 weeks. To induce knockout, mice received 2 × 10¹¹ genome copies of AAV8-CMV-Cre or AAV8-control. To test the role of Notch, mice were treated with 10 mg/kg of avagacestat for 4 weeks.RESULTSWe found that Kdm5b/Kdm5c knockout promoted alcohol-induced liver disease, whereas gonadectomy abolished this effect, suggesting that male sex hormones promote liver disease in the absence of KDM5 demethylases. In contrast, in the thioacetamide-induced fibrosis model, male sex hormones showed a protective effect regardless of genotype. In human liver disease samples, we found that androgen receptor expression positively correlated with fibrosis levels when KDM5B levels were low and negatively when KDM5B was high, suggesting that a KDM5B-dependent epigenetic state defines the androgen receptor role in liver fibrosis. Using isolated cells, we found that this difference was due to the differential effect of testosterone on hepatic stellate cell activation in the absence or presence of KDM5B/KDM5C. Moreover, this effect was mediated by KDM5-dependent suppression of Notch signaling. In KDM5-deficient mice, Notch3 and Jag1 gene expression was induced, facilitating testosterone-mediated induction of Notch signaling and stellate cell activation. Inhibiting Notch with avagacestat greatly reduced liver fibrosis and abolished the effect of Kdm5b/Kdm5c loss.CONCLUSIONSMale sex hormone signaling can promote or prevent alcohol-associated liver fibrosis depending on the KDM5-dependent epigenetic state.

31 Dec 2024·Cancer Biology & Therapy

M6A-mediated molecular patterns and tumor microenvironment infiltration characterization in nasopharyngeal carcinoma

Article

Author: Wang, Feng ; Peng, Lisha ; Wang, Yong

N6-methyladenosine (m6A) is the most predominant RNA epigenetic regulation in eukaryotic cells. Numerous evidence revealed that m6A modification exerts a crucial role in the regulation of tumor microenvironment (TME) cell infiltration in several tumors. Nevertheless, the potential role and mechanism of m6A modification in nasopharyngeal carcinoma (NPC) remains unknown. mRNA expression data and clinical information from GSE102349, and GSE53819 datasets obtained from Gene Expression Omnibus (GEO) was used for differential gene expression and subsequent analysis. Consensus clustering was used to identify m6A-related molecular patterns of 88 NPC samples based on prognostic m6A regulators using Univariate Cox analysis. The TME cell-infiltrating characteristics of each m6A-related subclass were explored using single-sample gene set enrichment (ssGSEA) algorithm and CIBERSORT algotithm. DEGs between two m6A-related subclasses were screened using edgeR package. The prognostic signature and predicated nomogram were constructed based on the m6A-related DEGs. The cell infiltration and expression of prognostic signature in NPC was determined using immunohistochemistry (IHC) analysis. Chi-square test was used to analysis the significance of difference of the categorical variables. And survival analysis was performed using Kaplan-Meier plots and log-rank tests. The NPC samples were divided into two m6A-related subclasses. The TME cell-infiltrating characteristics analyses indicated that cluster 1 is characterized by immune-related and metabolism pathways activation, better response to anit-PD1 and anti-CTLA4 treatment and chemotherapy. And cluster 2 is characterized by stromal activation, low expression of HLA family and immune checkpoints, and a worse response to anti-PD1 and anti-CTLA4 treatment and chemotherapy. Furthermore, we identified 1558 DEGs between two m6A-related subclasses and constructed prognostic signatures to predicate the progression-free survival (PFS) for NPC patients. Compared to non-tumor samples, REEP2, TMSB15A, DSEL, and ID4 were upregulated in NPC samples. High expression of REEP2 and TMSB15A showed poor survival in NPC patients. The interaction between REEP2, TMSB15A, DSEL, ID4, and m6A regulators was detected. Our finding indicated that m6A modification plays an important role in the regulation of TME heterogeneity and complexity.

01 Oct 2024·Translational Cancer Research

The role of SEC14L4 in esophageal squamous cell cancer: insights into clinical relevance and molecular pathways

Article

Author: Saeed, Anwaar ; Wan, Posum ; Wang, An ; Chen, Yanhui ; Wang, Youbo ; Chen, Xiaofeng ; Ma, Qinyun

BackgroundEsophageal squamous cell cancer (ESCC) is the most common type of esophageal cancer. This study aimed to elucidate the role of Saccharomyces cerevisiae-like 4 (SEC14L4) in ESCC.MethodsTo elucidate the role of SEC14L4 in ESCC, this study analyzed the clinical data, gene sequencing data, and other relevant data retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) of the National Center for Biotechnology Information. The methodology involved several analytical approaches, including nomogram model analysis, co-expression analysis, gene set enrichment and variation analysis, weighted correlation network analysis, drug susceptibility analysis, and single-cell analysis. These methods were employed to evaluate the significance of SEC14L4 in ESCC. The expression of SEC14L4 was evaluated via quantitative real-time polymerase chain reaction (qRT-PCR).ResultsSEC14L4 expression (P<0.001) was significantly elevated in those with ESCC, especially in patients with locally advanced disease (P=0.005), and indicated a poor prognosis (P=0.045). Findings from the nomogram model analysis identified the contribution of clinical indicators to survival prediction with good efficacy. Subsequently, the single-nucleotide polymorphisms and co-expressed genes of SEC14L4 were identified. Furthermore, pathways associated with SEC14L4, including DNA metabolic process, transcription factor binding, apoptosis, and others, were examined. Notably, SEC14L4 expression was predominantly observed in monocytes. Drug sensitivity analysis indicated the association of SEC14L4 expression with sensitivity of ESCC to the common chemotherapy drugs AICAR, BMS.708163, GNF.2, Nutlin.3a, PD.0325901, and RDEA119. Verification of the high expression of SEC14L4 in KYSE520 and KYSE150 was conducted, thereby confirming the study's findings.ConclusionsHigh expression of SEC14L4 is associated with poorer clinical outcomes, highlighting its potential as a therapeutic target and suggesting its involvement in the molecular mechanisms underlying ESCC.

100 Deals associated with Avagacestat

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External Link

KEGG	Wiki	ATC	Drug Bank
D09869	-	-	DB11893

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 2	Finland	Bristol Myers Squibb Co.	01 Feb 2009
Alzheimer Disease	Phase 2	United States	Bristol Myers Squibb Co.	01 Feb 2009
Alzheimer Disease	Phase 2	Denmark	Bristol Myers Squibb Co.	01 Feb 2009
Alzheimer Disease	Phase 2	Sweden	Bristol Myers Squibb Co.	01 Feb 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00890890 (Pubmed \| JAMA Neurol) Manual	Phase 2	Alzheimer Disease	263	Avagacestat	(crbpuajjlo) = ntswpulegm sodopuwpfc (auxthkzxyc )	Negative	01 Nov 2015
				Placebo	(crbpuajjlo) = qkulfrgscj sodopuwpfc (auxthkzxyc )
NCT00810147 (Pubmed)	Phase 2	Alzheimer Disease	209	Avagacestat 100 mg	jbpdrbjyoe(vjcuuqhbcg) = qeuaveoiui zrxzhoghxf (urjbzpncie )	-	01 Nov 2012
				Avagacestat 125 mg	jbpdrbjyoe(vjcuuqhbcg) = hyhiugghmr zrxzhoghxf (urjbzpncie )
AAIC2012	Not Applicable	CYP3A4 \| CYP2C9 \| CYP2C19	-	Avagacestat	(wudxzclqyr) = The most common AE in avagacestat-treated subjects in either study was headache sehazgflim (mxkvkiwror )	-	01 Jul 2012
				Clopidogrel
AAIC2011	Not Applicable	Alzheimer Disease Apo E genotype	175	BMS-708163	sbpvefoajr(nwonbrljqg) = abjzcvfpej zarjfdupai (ndkydnnefu ) View more	-	01 Jul 2011
AAIC2010	Not Applicable	-	-	BMS-708163 50 mg	(nfxzmpkefi) = srjxsvmeno vjosjeyewz (qsskwwtfyr )	-	01 Jul 2010
				BMS-708163 100 mg	(dwpzvmoyyt) = basavmljda zvgsdsaoyl (aiflkqqvjc ) View more
AAIC2010	Not Applicable	CSF Aβ	-	BMS-708163 50 mg	oqrmpqztmj(htqarqptic) = emrtwlavtg mmzoqklzdd (xdfksyphvz ) View more	-	01 Jul 2010
				BMS-708163 200 mg	oqrmpqztmj(htqarqptic) = jdnffqcoic mmzoqklzdd (xdfksyphvz ) View more