更新于：2024-11-01

GFRA2 x GFRα3

更新于：2024-11-01

基本信息

关联

项与 GFRA2 x GFRα3 相关的药物

GFRα2/3 inhibitors(Cerevel)

靶点

GFRA2 x GFRα3

作用机制

GFRA2 antagonists [+1]

在研机构

Cerevel Therapeutics LLC

原研机构

Cerevel Therapeutics LLC

在研适应症

疼痛 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 GFRA2 x GFRα3 相关的临床结果

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100 项与 GFRA2 x GFRα3 相关的转化医学

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0 项与 GFRA2 x GFRα3 相关的专利（医药）

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项与 GFRA2 x GFRα3 相关的文献（医药）

2024-09-01·Bioorganic & Medicinal Chemistry Letters

Discovery of the first selective, small-molecule GFRα2/3 inhibitors through DNA-encoded library technology

Article

作者: Missig, Galen ; Nguyen, Hanh Nho ; Ho, Tammy Szu-Yu ; Johnson, Shea L ; Choi-Sledeski, Yong Mi ; Lim, Jongwon ; Pin, Sokhom ; Toh, May Fern ; Gray, David ; Gupta, Kushali ; Ouk, Kosalvisal ; Wang, Minghua ; Stone, David J ; Barberis, Claude ; Zhang, Hongjun

Studies have shown that disrupting the formation of the ligand-RET-GFRα complex could be an effective way of treating pain and itch. Compared to traditional high-throughput screens, DNA encoded libraries (DELs) have distinguished themselves as a powerful technology for hit identification in recent years. The present work demonstrates the use of DEL technology identifying compound 16 as the first GFRa2/GFRa3 small molecule inhibitor (0.1/0.2 μM respectively) selective over RET. This molecule represents an opportunity to advance the development of small-molecule inhibitors targeting the GFRα-RET interface for the treatment of pain and itch.

2019-07-14·World Journal of Gastroenterology3区 · 医学

Identification of differentially expressed genes regulated by methylation in colon cancer based on bioinformatics analysis

3区 · 医学

Article

作者: Dai, Dong-Qiu ; Liang, Yu ; Zhang, Cheng

BACKGROUNDDNA methylation, acknowledged as a key modification in the field of epigenetics, regulates gene expression at the transcriptional level. Aberrant methylation in DNA regulatory regions could upregulate oncogenes and downregulate tumor suppressor genes without changing the sequences. However, studies of methylation in the control of gene expression are still inadequate. In the present research, we performed bioinformatics analysis to clarify the function of methylation and supply candidate methylation-related biomarkers and drivers for colon cancer.AIMTo identify and analyze methylation-regulated differentially expressed genes (MeDEGs) in colon cancer by bioinformatics analysis.METHODSWe downloaded RNA expression profiles, Illumina Human Methylation 450K BeadChip data, and clinical data of colon cancer from The Cancer Genome Atlas project. MeDEGs were identified by analyzing the gene expression and methylation levels using the edgeR and limma package in R software. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed in the DAVID database and KEGG Orthology-Based Annotation System 3.0, respectively. We then conducted Kaplan-Meier survival analysis to explore the relationship between methylation and expression and prognosis. Gene set enrichment analysis (GSEA) and investigation of protein-protein interactions (PPI) were performed to clarify the function of prognosis-related genes.RESULTSA total of 5 up-regulated and 81 down-regulated genes were identified as MeDEGs. GO and KEGG pathway analyses indicated that MeDEGs were enriched in multiple cancer-related terms. Furthermore, Kaplan-Meier survival analysis showed that the prognosis was negatively associated with the methylation status of glial cell-derived neurotrophic factor (GDNF) and reelin (RELN). In PPI networks, GDNF and RELN interact with neural cell adhesion molecule 1. Besides, GDNF can interact with GDNF family receptor alpha (GFRA1), GFRA2, GFRA3, and RET. RELN can interact with RAFAH1B1, disabled homolog 1, very low-density lipoprotein receptor, lipoprotein receptor-related protein 8, and NMDA 2B. Based on GSEA, hypermethylation of GDNF and RELN were both significantly associated with pathways including "RNA degradation," "ribosome," "mismatch repair," "cell cycle" and "base excision repair."CONCLUSIONAberrant DNA methylation plays an important role in colon cancer progression. MeDEGs that are associated with the overall survival of patients may be potential targets in tumor diagnosis and treatment.

2018-10-01·Leukemia1区 · 医学

RET-mediated autophagy suppression as targetable co-dependence in acute myeloid leukemia

1区 · 医学

Article

作者: Rudat, S ; Göllner, S ; Müller-Tidow, C ; Fröhling, S ; Wickenhauser, C ; Scholl, C ; Milsom, M D ; Pfaus, A ; Ellegast, J M ; Bühler, C ; Martinez, E ; Cheng, Y Y ; Lutz, C ; Holtmann, J ; Bullinger, L ; Sykes, S M ; Marcantonio, D Di

Many cases of AML are associated with mutational activation of receptor tyrosine kinases (RTKs) such as FLT3. However, RTK inhibitors have limited clinical efficacy as single agents, indicating that AML is driven by concomitant activation of different signaling molecules. We used a functional genomic approach to identify RET, encoding an RTK, as an essential gene in multiple subtypes of AML, and observed that AML cells show activation of RET signaling via ARTN/GFRA3 and NRTN/GFRA2 ligand/co-receptor complexes. Interrogation of downstream pathways identified mTORC1-mediated suppression of autophagy and subsequent stabilization of leukemogenic drivers such as mutant FLT3 as important RET effectors. Accordingly, genetic or pharmacologic RET inhibition impaired the growth of FLT3-dependent AML cell lines and was accompanied by upregulation of autophagy and FLT3 depletion. RET dependence was also evident in mouse models of AML and primary AML patient samples, and transcriptome and immunohistochemistry analyses identified elevated RET mRNA levels and co-expression of RET and FLT3 proteins in a substantial proportion of AML patients. Our results indicate that RET-mTORC1 signaling promotes AML through autophagy suppression, suggesting that targeting RET or, more broadly, depletion of leukemogenic drivers via autophagy induction provides a therapeutic opportunity in a relevant subset of AML patients.