Last update 01 Nov 2024

PI3K family x Syk

Last update 01 Nov 2024

Basic Info

Related Targets

PI3K familySyk

Drugs associated with PI3K family x Syk

MTX-216

Target

PI3K family x Syk

Mechanism

Phosphatidylinositol 3-kinase family inhibitors [+1]

Active Org.

Midatech Ltd.

Originator Org.

Midatech Ltd.

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SRX-3207

Target

PI3K family x Syk

Mechanism

Phosphatidylinositol 3-kinase family inhibitors [+1]

Active Org.-

Originator Org.

SignalRx Pharmaceuticals, Inc.

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with PI3K family x Syk

100 Translational Medicine associated with PI3K family x Syk

0 Patents (Medical) associated with PI3K family x Syk

323

Literatures (Medical) associated with PI3K family x Syk

01 Dec 2024·Computational Biology and Chemistry

Genetic regulation of B cell receptor signaling pathway: Insights from expression quantitative trait locus analysis using a mixed model

Article

Author: Bae, Hojin ; Jeon, Hyowon ; Lee, Chaeyoung

The B cell receptor (BCR) signaling pathway regulates non-immune cellular response through various pathways like MAPK, NF-kB, and PI3K-Akt. This study aimed to identify expression quantitative trait loci (eQTL) and their regulatory functions on BCR signaling pathway genes. A mixed model was employed to analyze eQTL using RNA expression levels in lymphoblastoid from 376 Europeans in the GEUVADIS dataset. In total, 266 SNPs, including 115 cis-acting SNPs, were found for association with transcription of 13 genes (P < 5 × 10^-8), revealing 19 independent signals for five genes through linkage disequilibrium analysis. Functional analysis, aligning them with DNase sensitive sites, transcription factor binding sites, histone modification, promoters/enhancers, CpG islands, and ChIA-PET, identified regulatory variants targeting SYK, VAV2, and PLCG2. Notably, rs2562397 was validated as a SYK promoter variant, and rs694505, rs636667, and rs4889409 were confirmed as enhancer variants for VAV2 and PLCG2. Their allelic differences in gene expression were also confirmed using ENCODE ChIP-seq and Sei neural network prediction. Persistent differential expression of these genes by alleles might impact the adaptive immune system, vascular development, and/or relevant diseases that have been previously associated with other variants of the genes. Comprehensive genetic architecture studies of the BCR signaling pathway, along with experiments demonstrating related mechanisms, will greatly contribute to understanding the underlying mechanisms of relevant disease development and implementing precision medicine.

01 Jul 2024·Journal of Ethnopharmacology

Deciphering the pharmacological mechanisms of Shenlingbaizhu formula in antibiotic-associated diarrhea treatment: Network pharmacological analysis and experimental validation

Article

Author: Chen, Yan ; Zhu, Wanhong ; Meng, Xiangmei ; Li, Yuhang ; Liao, Mengting ; Gu, Yixiao ; Ding, Xia ; Li, Tao ; Zheng, Haocheng ; Wang, Sici ; Guo, Shuzhen ; Lin, Jie

ETHNOPHARMACOLOGICAL RELEVANCEShenlingbaizhu (SLBZ) formula, a classical traditional Chinese medicinal (TCM) formula, has been widely used for treating antibiotic-associated diarrhea (AAD). However, the underlying pharmacological mechanisms have not yet been investigated thoroughly.AIM OF THE STUDYTo explore the remission mechanism of SLBZ in the treatment of AAD, we conducted network pharmacological analysis and experimental validation in vitro and in vivo.MATERIALS AND METHODSIn this study, the main compounds of SLBZ were identified by ultra-high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) and online databases. The targets of the active components and AAD-related targets were predicted by network pharmacology, and the potential targets of SLBZ against AAD were obtained. Then the core targets were recognized after Protein-Protein Interaction (PPI) analysis. Based on these, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analyses were conducted, and the key pathway was screened. Subsequently, molecular docking was performed using Auto Dock Vina to find the key components that played a crucial role in that pathway. Molecular dynamics simulation was performed by Gromacs software to detect the binding mode. Finally, the results were confirmed by in vitro and in vivo experiments.RESULTSA total of 66 active ingredients of SLBZ were detected by UHPLC-MS, and 128 active ingredients were screened out by network pharmacological analysis. Additionally, 935 drug targets and 1686 AAD-related targets were obtained. Seventy-eight intersected genes were selected as potential therapeutic targets and 19 genes were excavated as core targets. Enrichment analysis revealed PI3K-AKT signaling pathway was the key pathway in SLBZ against AAD. Topological analysis further revealed that JAK2, MTOR, TLR4, and SYK were the key targets affected by SLBZ on the PI3K-AKT pathway, and 52 components of SLBZ were associated with them. Molecular docking and dynamics simulation revealed strong binding affinities between MTOR and diosgenin. Subsequently, after SLBZ treatment, the expression levels of JAK2, MTOR, TLR4, and SYK were found significantly upregulated in the AAD model rats (p < 0.05). The cell experiment further validated the good binding ability between MTOR and diosgenin.CONCLUSIONWe demonstrate that the therapeutic effect of SLBZ on AAD was achieved in part by inhibiting the PI3K-AKT pathway.

01 May 2024·Heliyon

Transcriptome analysis reveals PRKCA as a potential therapeutic target for overcoming cisplatin resistance in lung cancer through ferroptosis

Article

Author: Wang, Binhui ; Ouyang, Songyun ; Zhang, Qingyi ; Zhao, Chunling ; Sun, Ting ; Zhou, Xiaolei ; Liu, Fenghui ; Chen, Ruiying ; Zhao, Qitai ; Zhang, Penghua ; Ma, Xiaohua

Cisplatin-based chemotherapy is the current standard care for lung cancer patients; however, drug resistance frequently develops during treatment, thereby limiting therapeutic efficacy.The molecular mechanisms underlying cisplatin resistance remain elusive. In this study, we conducted an analysis of microarray data from the Gene Expression Omnibus (GEO) database under the accession numbers GSE21656, which encompassed expression profiling of cisplatin-resistant H460 (DDP-H460)and the parental cells (H460). Subsequently, we calculated the differentially expressed genes (DEGs) between DDP-H460 and H460. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs demonstrated significant impact on the Rap1, PI3K/AKT and MAPK signaling pathways. Moreover, protein and protein interaction (PPI) network analysis identified PRKCA, DET1, and UBE2N as hub genes that potentially contribute predominantly to cisplatin resistance. Ultimately, PRKCA was selected for validation due to its significant prognostic effect, which predicts unfavorable overall survival and disease-free survival in patients with lung cancer. Network analysis conducted on The Cancer Genome Atlas (TCGA) database revealed a strong gene-level correlation between PRKCA and TP53, CDKN2A, BYR2, TTN, KRAS, and PIK3CA; whereas at the protein level, it exhibited a high correlation with EGFR, Lck, Bcl2, and Syk. The in vitro experiments revealed that PRKCA was upregulated in the cisplatin-resistant A549 cells (DDP-A549), while knockdown of PRKCA increased DDP-A549 apoptosis upon cisplatin treatment. Moreover, we observed that PRKCA knockdown attenuated DDP-A549 proliferation, migration and invasion ability. Western blot analysis demonstrated that PRKCA knockdown downregulated phosphorylation of PI3K expression while upregulated the genes involved in ferroptosis signaling. In summary, our results elucidate the role of PRKCA in acquiring resistance to cisplatin and underscore its potential as a therapeutic target for cisplatin-resistant lung cancer.

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