更新于：2024-11-01

ARHGEF4

更新于：2024-11-01

基本信息

别名

APC-stimulated guanine nucleotide exchange factor 1、ARHGEF4、ASEF

+ [4]

简介

Acts as guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases. Binding of APC may activate RAC1 GEF activity. The APC-ARHGEF4 complex seems to be involved in cell migration as well as in E-cadherin-mediated cell-cell adhesion. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression.

关联

项与 ARHGEF4 相关的药物

MAI-400

靶点

ARHGEF4

作用机制

ARHGEF4 inhibitors

在研机构

上海交通大学医学院

原研机构

上海交通大学医学院

在研适应症

结直肠癌

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 ARHGEF4 相关的临床结果

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100 项与 ARHGEF4 相关的转化医学

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0 项与 ARHGEF4 相关的专利（医药）

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项与 ARHGEF4 相关的文献（医药）

2024-06-01·Acta Pharmaceutica Sinica B

Computer-aided molecular design and optimization of potent inhibitors disrupting APC‒Asef interaction

Article

作者: Shi, Ting ; Wang, Junyuan ; Song, Kun ; Liu, Chen-Ying ; Yang, Xiuyan ; Zhong, Jie ; Zhang, Jian ; Du, Zeqian ; Yu, Jianqiang ; Guo, Yuegui ; Wang, Xuefei

Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. At initial diagnosis, approximately 20% of patients are diagnosed with metastatic CRC (mCRC). Although the APC‒Asef interaction is a well-established target for mCRC therapy, the discovery and development of effective and safe drugs for mCRC patients remains an urgent and challenging endeavor. In this study, we identified a novel structural scaffold based on MAI inhibitors, the first-in-class APC‒Asef inhibitors we reported previously. ONIOM model-driven optimizations of the N-terminal cap and experimental evaluations of inhibitory activity were performed, and 24-fold greater potency was obtained with the best inhibitor compared to the parental compound. In addition, the cocrystal structure validated that the two-layer π‒π stacking interactions were essential for inhibitor stabilization in the bound state. Furthermore, in vitro and in vivo studies have demonstrated that novel inhibitors suppressed lung metastasis in CRC by disrupting the APC‒Asef interaction. These results provide an intrinsic structural basis to further explore drug-like molecules for APC‒Asef-mediated CRC therapy.

2023-12-01·Placenta

High placental expression of FLT1, LEP, PHYHIP and IL3RA – In persons of African ancestry with severe preeclampsia

Article

作者: Jacobs, Marni B ; Fisch, Kathleen M ; Laurent, Louise C ; Pizzo, Donald ; Nasamran, Chanond A ; Lamale-Smith, Leah ; Bui, Tony ; Morey, Robert ; St Louis, Hailee ; Aisagbonhi, Omonigho ; Meads, Morgan ; Horii, Mariko ; Magallanes, Celestine ; Mulholland, Megan

INTRODUCTIONMortality from preeclampsia (PE) and PE-associated morbidities are 3-to 5-fold higher in persons of African ancestry than in those of Asian and European ancestries.METHODSTo elucidate placental contribution to worse PE outcomes in African ancestry pregnancies, we performed bulk RNA sequencing on 50 placentas from persons with severe PE (sPE) of African (n = 9), Asian (n = 18) and European (n = 23) ancestries and 73 normotensive controls of African (n = 10), Asian (n = 15) and European (n = 48) ancestries.RESULTSPreviously described canonical preeclampsia genes, involved in metabolism and hypoxia/angiogenesis including: LEP, HK2, FSTL3, FLT1, ENG, TMEM45A, ARHGEF4 and HTRA1 were upregulated sPE versus normotensive placentas across ancestries. LTF, NPR3 and PHYHIP were higher in African vs. Asian ancestry sPE placentas. Allograft rejection/adaptive immune response genes were upregulated in placentas from African but not in Asian or European ancestry sPE patients; IL3RA was of particular interest because the patient with the highest placental IL3RA expression, a person of African ancestry with sPE, developed postpartum cardiomyopathy, and was the only patient out of 123, that developed this condition. Interestingly, the sPE patients with the highest IL3RA expression among persons of Asian and European ancestries developed unexplained tachycardia peripartum, necessitating echocardiography in the European ancestry patient. The association between elevated placental IL3RA levels and unexplained tachycardia or peripartum cardiomyopathy was found to be significant in the 50 sPE patients (p = .0005).DISCUSSIONHigh placental upregulation of both canonical preeclampsia and allograft rejection/adaptive immune response genes may contribute to worse PE outcomes in African ancestry sPE patients.

2022-08-01·Gene

A bioinformatics-based study on the Cisplatin-resistant lung cancer cells; what are the orchestrators of this phenom?

Article

作者: Baradaran, Behzad ; Moslemi, Mohammadreza ; Haddad, Sara ; Khalaji, Amirreza ; Yazdani, Yalda ; Alizadeh, Leila

Lung cancer represents a significant global health issue and is among the central causes of mortality and morbidity around the world. Unfortunately, the majority of lung cancer patients acquire drug resistant to chemotherapy either intrinsically or acquired after Cisplatin treatment. It is indicated that increasing or decreasing the expression of particular genes can affect chemotherapeutic sensitivity or resistance. As a result, gaining a deeper knowledge of the changed expression of genes implicated in lung cancer drug resistance, as well as developing novel therapeutic techniques, are critical targets for continued advancement in lung cancer treatment. In the present study, we aimed to find key regulatory genes in the progression of Cisplatin resistance in A-549 lung cancer cells. In this regard, microarray dataset of Cisplatin-resistant and Cisplatin-sensitive was retrieved from the Gene Expression Omnibus (GEO) with accession number of GSE108214. Then, differentially expressed genes (DEGs) between sensitive and resistant lung cancer cells were obtained by using R software v4.0.2 and related packages. We recognized CEACAM1, DGKA, ARHGEF4, and THSD4 are involved in the drug resistance. Experimentally, Cisplatin-resistant A-549 cells were developed and analyzed by MTT assay. Besides, the expression of candidate genes were analyzed in these cells compared to Cisplatin-sensitive A-549 cells by qRT-PCR. The findings presented that the expression of CEACAM1, DGKA, ARHGEF4, and THSD4 was altered following the induction of Cisplatin resistance in A549 cells.