Emergence of a Promising Lead Compound in the Treatment of Triple Negative Breast Cancer: An Insight into Conformational Features and Ligand Binding Landscape of c-Src Protein with UM-164

Ndagi, Umar; Mhlongo, Ndumiso N.; Soliman, Mahmoud E. S.

doi:10.1007/s12010-017-2677-z

Cited by 10 publications

(7 citation statements)

References 44 publications

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“…[ 33 ] In vitro experiments show that increased SRC kinase activity can promote breast cancer invasiveness. [ 34 ] Importantly, some SRC inhibitors have been developed for targeted therapy of TNBC, [ 35 ] so we consider that SRC is a target gene in TNBC, and we need to further study targeted therapy for the SRC, as well as prevent the occurrence and early diagnosis of TNBC.…”

Section: Discussionmentioning

confidence: 99%

KEGG-expressed genes and pathways in triple negative breast cancer

Chen¹,

Liu²,

Cen³

et al. 2020

Medicine

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Background: The incidence of triple negative breast cancer (TNBC) is at a relatively high level, and our study aimed to identify differentially expressed genes (DEGs) in TNBC and explore the key pathways and genes of TNBC. Methods: The gene expression profiling (GSE86945, GSE86946 and GSE102088) data were obtained from Gene Expression Omnibus Datasets, DEGs were identified by using R software, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs were performed by the Database for Annotation, Visualization and Integrated Discovery (DAVID) tools, and the protein-protein interaction (PPI) network of the DEGs was constructed by the STRING database and visualized by Cytoscape software. Finally, the survival value of hub DEGs in breast cancer patients were performed by the Kaplan–Meier plotter online tool. Results: A total of 2998 DEGs were identified between TNBC and health breast tissue, including 411 up-regulated DEGs and 2587 down-regulated DEGs. GO analysis results showed that down-regulated DEGs were enriched in gene expression (BP), extracellular exosome (CC), and nucleic acid binding, and up-regulated were enriched in chromatin assembly (BP), nucleosome (CC), and DNA binding (MF). KEGG pathway results showed that DEGs were mainly enriched in Pathways in cancer and Systemic lupus erythematosus and so on. Top 10 hub genes were picked out from PPI network by connective degree, and 7 of top 10 hub genes were significantly related with adverse overall survival in breast cancer patients ( P < .05). Further analysis found that only EGFR had a significant association with the prognosis of triple-negative breast cancer ( P < .05). Conclusions: Our study showed that DEGs were enriched in pathways in cancer, top 10 DEGs belong to up-regulated DEGs, and 7 gene connected with poor prognosis in breast cancer, including HSP90AA1 , SRC , HSPA8 , ESR1 , ACTB , PPP2CA , and RPL4 . These can provide some guidance for our research on the diagnosis and prognosis of TNBC, and further research is needed to evaluate their value in the targeted therapy of TNBC.

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Section: Discussionmentioning

confidence: 99%

KEGG-expressed genes and pathways in triple negative breast cancer

Chen¹,

Liu²,

Cen³

et al. 2020

Medicine

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“…From the MM-PBSA approach, the binding free energies were obtained for both 3CLpro/PLpro–CS1 and 3CLpro/PLpro–CS2 complexes. This analysis provides a better understanding of various energy contributions such as entropy and enthalpy of the molecular recognition [ 52 , 53 ]. For 600 ns trajectories, we considered 1000 snapshots during the binding free energy calculation.…”

Section: Methodsmentioning

confidence: 99%

Insights into the Dynamics and Binding of Two Polyprotein Substrate Cleavage Points in the Context of the SARS-CoV-2 Main and Papain-like Proteases

Sanusi

Lobb

2022

Molecules

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It is well known that vital enzymes in the replication process of the coronavirus are the SARS-CoV-2 PLpro and SARS-CoV-2 3CLpro, both of which are important targets in the search for anti-coronavirus agents. These two enzymes are responsible for cleavage at various polyprotein sites in the SARS-CoV-2 lifecycle. Herein, the dynamics of the polyprotein cleavage sequences for the boundary between non-structural proteins Nsp1 and Nsp2 (CS1) and between Nsp2 and Nsp3 (CS2) in complex with both the papain-like protein PLpro and the main protease 3CLpro were explored using computational methods. The post dynamics analysis reveals that CS1 and CS2 both have greater stability when complexed with PLpro. Of these two, greater stability is observed for the CS1–PLpro complex, while destabilization resulting in loss of CS2 from the PLpro active site is observed for CS2-PLpro, suggesting the rate of exchange by the papain-like protease is faster for CS2 compared to CS1. On the other hand, the 3CLpro main protease also reveals stability for CS1 suggesting that the main protease could also play a potential role in the cleavage at point CS1. However, destabilization occurs early in the simulation for the complex CLpro–CS2 suggesting a poor interaction and non-plausible protease cleavage of the polyprotein at CS2 by the main protease. These findings could be used as a guide in the development and design of potent COVID-19 antiviral inhibitors that mimic the CS1 cleavage site.

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“…Combining Src inhibitors with compounds targeting other key regulators or signaling pathways, such as BI2536 (PLK1 inhibitor), KX2-361 (Tubulin inhibitor) and JSI-124 (STAT3 inhibitor), has achieved notable consequences for glioma treatment in vitro and in vivo [ 23 , 24 , 25 , 26 ]. UM-164 (also known as DAS-DFGO-II) is a highly potent c-Src inhibitor that can bind to the inactive kinase conformation of c-Src and is more potent than Dasatinib in its Src active site binding ability [ 27 ]. Because UM-164 can alter c-Src localization in triple negative breast cancer (TNBC) cells and displays anti-TNBC cell proliferative activity, UM-164 is a promising lead compound for the treatment of TNBC [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

UM-164, a Dual Inhibitor of c-Src and p38 MAPK, Suppresses Proliferation of Glioma by Reducing YAP Activity

Zhang

Liu

et al. 2022

Cancers

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UM-164 is a dual inhibitor of c-Src and p38 MAPK, and has been a lead compound for targeting triple-negative breast cancer. UM-164 shows stronger binding to the active sites of Src compared with the conventional Src inhibitor Dasatinib. While Dasatinib has displayed some inhibitory effects on glioma growth in clinical trials, whether UM-164 can suppress glioma growth has not been reported. Here we show that UM-164 suppressed the proliferation, migration and spheroid formation of glioma cells, and induced cell cycle arrest in the G1 phase. Moreover, UM-164 triggered YAP translocation to the cytoplasm and reduced the activity of YAP, as evidenced by a luciferase assay. Accordingly, UM-164 markedly decreased the expression levels of YAP target genes CYR61 and AXL. Importantly, ectopic expression of wild-type YAP or YAP-5SA (YAP constitutively active mutant) could rescue the anti-proliferative effect induced by UM-164. Intriguingly, p38 MAPK appears to play a greater role than Src in UM-164-mediated inhibition of YAP activity. Furthermore, the in vitro anti-glioma effect mediated by UM-164 was confirmed in a xenograft glioma model. Together, these findings reveal a mechanism by which UM-164 suppresses the malignant phenotypes of glioma cells and might provide a rationale for UM-164-based anti-glioma clinical trials.

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Emergence of a Promising Lead Compound in the Treatment of Triple Negative Breast Cancer: An Insight into Conformational Features and Ligand Binding Landscape of c-Src Protein with UM-164

Cited by 10 publications

References 44 publications

KEGG-expressed genes and pathways in triple negative breast cancer

KEGG-expressed genes and pathways in triple negative breast cancer

Insights into the Dynamics and Binding of Two Polyprotein Substrate Cleavage Points in the Context of the SARS-CoV-2 Main and Papain-like Proteases

UM-164, a Dual Inhibitor of c-Src and p38 MAPK, Suppresses Proliferation of Glioma by Reducing YAP Activity

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