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Last update 08 May 2025

ARHGEF4

Last update 08 May 2025

Basic Info

Synonyms

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

+ [4]

Introduction

Acts as a 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.

Drugs associated with ARHGEF4

MAI-400

Target

ARHGEF4

Mechanism

ARHGEF4 inhibitors

Active Org.-

Originator Org.

Shanghai Jiao Tong University School of Medicine

Active Indication-

Inactive Indication

Colorectal Cancer

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ARHGEF4

100 Translational Medicine associated with ARHGEF4

0 Patents (Medical) associated with ARHGEF4

Literatures (Medical) associated with ARHGEF4

01 Jun 2024·Acta Pharmaceutica Sinica B

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

Article

Author: 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.

01 Dec 2023·Placenta

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

Article

Author: 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.

01 Jul 2023·iScience

Whole-genome DNA methylation and DNA methylation-based biomarkers in lung squamous cell carcinoma

Article

Author: Qian, Banglun ; Shi, Shuai ; Peng, Weilin ; Wang, Xiang ; Tu, Guangxu ; He, Boxue ; Cai, Qidong ; Peng, Shaoliang ; Liang, Qingchun ; Tao, Yongguang

Exploring early detection methods through comprehensive evaluation of DNA methylation for lung squamous cell carcinoma (LUSC) patients is of great significance. By using different machine learning algorithms for feature selection and model construction based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, five methylation biomarkers in LUSC (along with mapped genes) were identified including cg14823851 (TBX4), cg02772121 (TRIM15), cg10424681 (C6orf201), cg12910906 (ARHGEF4), and cg20181079 (OR4D11), achieving extremely high sensitivity and specificity in distinguishing LUSC from normal samples in independent cohorts. Pyrosequencing assay verified DNA methylation levels, meanwhile qRT-PCR and immunohistochemistry results presented their accordant methylation-related gene expression statuses in paired LUSC and normal lung tissues. The five methylation-based biomarkers proposed in this study have great potential for the diagnosis of LUSC and could guide studies in methylation-regulated tumor development and progression.

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ARHGEF4

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