Eg5 targeting agents: From new anti-mitotic based inhibitor discovery to cancer therapy and resistance

Garcia-Saez, I.; Skoufias, Dimitrios A.

doi:10.1016/j.bcp.2020.114364

Cited by 71 publications

(51 citation statements)

References 163 publications

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“…The kinesin family member 11 (KIF11) gene was identified as a hub gene in LUAD tissues. KIF11 belongs to the kinesin superfamily, is involved in spindle dynamics, and encodes a molecular motor protein known as Eg5, which is involved in chromosome positioning, chromosome separation, bipolar spindle construction, and driving mitosis to promote cellular proliferation (9,10). For non-mitotic cells, Eg5 also mediates the transport of secretory proteins from the Golgi complex to the cell surface (11).…”

Section: Introductionmentioning

confidence: 99%

KIF11 Serves as an Independent Prognostic Factor and Therapeutic Target for Patients With Lung Adenocarcinoma

et al. 2021

Front. Oncol.

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BackgroundLung adenocarcinoma (LUAD) is challenging in clinical practice due to the poor understanding of molecular mechanisms and limited therapeutic targets. Herein, the work aimed to use bioinformatics to identify a promising molecular target for LUAD therapy.MethodsDifferentially expressed genes (DEGs) from the Cancer Genome Atlas (TCGA) dataset were used for a weighted gene co-expression network analysis (WGCNA) to screen the hub gene. After a prognostic estimation with meta-analysis and COX regression analysis, we performed a function analysis on the corresponding gene. The ESTIMATE and CIBERSORT methods were adopted to analyze the association of the hub gene with the tumor microenvironment (TME). A cohort of functional assays was conducted to establish the functional roles of the hub gene in A549 and PC-9 cells.ResultsOur screen identified KIF11 as a prognostic factor, which indicated the poor overall survival and the worse progression-free survival in LUAD patients. Additionally, KIF11 was primarily involved in cell cycle, TME alteration and tumor-infiltrating immune cells proportions. KIF11 knockdown exerted inhibitory effects on cell proliferation, migration, and invasion. Results of the flow cytometry analysis revealed that KIF11 knockdown induced a G2/M phase arrest and improved apoptosis in LUAD cells.ConclusionsKIF11 is essential for LUAD cell proliferation and metastasis, and it may serve as an independent prognostic factor as well as a promising therapeutic target for LUAD patients.

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Section: Introductionmentioning

confidence: 99%

KIF11 Serves as an Independent Prognostic Factor and Therapeutic Target for Patients With Lung Adenocarcinoma

et al. 2021

Front. Oncol.

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“…This mechanism may also explain the greater selectivity to tumor cells found for the investigated Pt(II) alkylpyrazole complexes compared to cisplatin because healthy cells do not divide or divide significantly more slowly. Eg5 is becoming an increasingly attractive therapeutic target for the treatment of cancer by chemotherapeutics [ 57 ]. Hence, the introduction of cis-Pt(II) alkylpyrazole complexes in this work may be an incentive to search for new anticancer chemotherapeutics derived from platinum complexes with this mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Novel cis‐Pt(II) Complexes with Alkylpyrazole Ligands: Synthesis, Characterization, and Unusual Mode of Anticancer Action

Kašpárková

Kostrhunová

Novohradský

et al. 2022

Bioinorganic Chemistry and Applications

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One concept of improving anticancer effects of conventional platinum-based antitumor drugs consists of conjugating these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, physicochemical characterization, biological effects, and mechanisms of action of four new analogs of conventional cisplatin, namely, cis-Pt(II) complexes containing either methyl or ethyl pyrazole N-donor ligands and chlorido or iodido ligands. It is noteworthy that while chlorido complexes display activity in a variety of cancer cell lines comparable to cisplatin, iodido complexes are considerably more potent due to their enhanced hydrophobicity and consequently enhanced cellular accumulation. Moreover, all of the studied Pt(II) alkylpyrazole complexes display a higher selectivity for tumor cells and effectively overcome the acquired resistance to cisplatin. Further results focused on the mechanism of action of the studied complexes and showed that in contrast to cisplatin and several platinum-based antitumor drugs, DNA damage by the investigated Pt(II)-alkylpyrazole complexes does not play a major role in their mechanism of action. Our findings demonstrate that inhibition of the tubulin kinesin Eg5, which is essential for forming a functional mitotic spindle, plays an important role in their mechanism of antiproliferative action.

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“…When its activity is inhibited, the bipolar spindle fails to assemble and a monopolar spindle forms, thus resulting in cell death. Based on these findings, different Eg5 inhibitors were synthesized and tested in in vitro cancer models, and the most promising have entered clinical trials [ 23 , 24 , 25 , 26 ], such as the dihydropyrimidine scaffold-based [ 27 , 28 ], quinazolinones [ 26 ], chromen-4-ones [ 29 ], benzimidazoles [ 30 ], and thiadiazolines [ 31 ]. Some inhibitors are also highlighted in the protein–chemical network maps obtained through the STITCH tool [ 32 ] and reported in Supporting Information in Figure S3 .…”

Section: Introductionmentioning

confidence: 99%

Negative Modulation of the Angiogenic Cascade Induced by Allosteric Kinesin Eg5 Inhibitors in a Gastric Adenocarcinoma In Vitro Model

et al. 2022

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Eg5 is a kinesin essential in bipolar spindle formation, overexpressed in tumours, thus representing a new target in cancer therapy. We aimed at evaluating the anti-cancer activity of Eg5 thiadiazoline inhibitors 2 and 41 on gastric adenocarcinoma cells (AGS), focusing on the modulation of angiogenic signalling. Docking studies confirmed a similar interaction with Eg5 to that of the parent compound K858. Thiadiazolines were also tested in combination with Hesperidin (HSD).

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Eg5 targeting agents: From new anti-mitotic based inhibitor discovery to cancer therapy and resistance

Cited by 71 publications

References 163 publications

KIF11 Serves as an Independent Prognostic Factor and Therapeutic Target for Patients With Lung Adenocarcinoma

KIF11 Serves as an Independent Prognostic Factor and Therapeutic Target for Patients With Lung Adenocarcinoma

Novel cis‐Pt(II) Complexes with Alkylpyrazole Ligands: Synthesis, Characterization, and Unusual Mode of Anticancer Action

Negative Modulation of the Angiogenic Cascade Induced by Allosteric Kinesin Eg5 Inhibitors in a Gastric Adenocarcinoma In Vitro Model

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