barasertib (AZD1152)

Lung adenocarcinoma patients have poorer prognosis due to higher levels of CPCs, TMPO-AS1, and E2F1. A sponge complex between TMPO-AS1 and hsa-let-7b-5p may contribute to the tumor progression, and targeting CPCs with natural compounds could offer therapeutic potential. Highlights 1. The overexpression of chromosomal passenger complex genes, AURKB, BIRC5, CDCA8, and INCENP is significantly associated with poor prognosis in lung adenocarcinoma (LUAD), particularly among smokers. 2. The competing endogenous RNA (ceRNA) axis, which involves the long non-coding RNA TMPO-AS1 and the miRNA hsa-let-7b-5p, regulates the expression of these CPC genes. TMPO-AS1 shows a positive correlation with CPC genes, while hsa-let-7b-5p shows a negative correlation. 3. Survival analysis indicates that the combined expression of CPC genes, TMPO-AS1, hsa-let-7b-5p, and E2F1 may serve as a reliable prognostic biomarker panel for LUAD in smokers. 4. Hesperidin exhibits a strong binding affinity to CPC proteins, particularly AURKB, when compared to Barasertib, Docetaxel, and Paclitaxel, highlighting its potential as a therapeutic agent. 5. The overexpression of CPC genes, E2F1, and TMPO-AS1 in LUAD is strongly associated with reduced infiltration of CD4⁺ T cells, indicating their role in promoting an immunosuppressive tumor microenvironment.

CDK4/6i-resistant cell lines (MCF7rR, MCF7rA, MCF7rP, T47DrR, T47DrA, and T47DrP) were isolated and evaluated for their aggressive phenotypes, cross-resistance, transcriptomic changes, and sensitivity to volasertib (PLK1 inhibitor) and barasertib (AukB inhibitor). We conclude that cell cycle upregulation leading to G2/M progression is a key route for CDK4/6i resistance. AukB or PLK1 inhibitors that block G2/M phase could be a promising strategy.

Overall, compound 18 is a valuable chemical biology tool and a potential therapeutic. Our findings suggest that pharmacological degradation of AURKB could offer an alternative therapeutic approach for treating AURKB-dependent tumors.

Alisertib and barasertib emerge as potential in vitro candidates against MM, although further studies are needed to validate their efficacy and to find the best combinations with other molecules.

Finally, our drug screening identified barasertib, an aurora kinase inhibitor, as a triple-combination candidate with epidermal growth factor receptor-tyrosine kinase inhibitors and XAV-939 for MYC+ cells. This study demonstrates the utility of longitudinal pharmacogenomic analysis to develop treatment strategies according to individual tumor evolution type. The study underscores the importance of integrating genomic and pharmacogenomic profiling in clinical practice to tailor treatments according to tumor evolution type.

Barasertib (AZD2811) targets the mitotic kinase Aurora B (AURKB) and is in current clinical trials for various cancers. Lastly, we found in two different p53 mutated cell line tumor models that barasertib plus A196 has greater anti-tumor activity than either single agent. Our results suggest co-targeting of AURKB and SUV4-20H1/2 could be effective against p53-mutated or deficient cancers, including TNBCs in which approximately 80% of cases are p53 mutated.

Synthetic inhibitors like AZD1152 and ZM447439 show selectivity for AURKB but often lack specificity due to high homology within the aurora kinase family. The study also noted transitions in the overall protein secondary structures, such as turn to coil, coil to sheet, and coil to helix, contributing to a stable structure upon EGCG binding. These findings highlight the complex interplay between EGCG and AURKB, providing insights into the conformational dynamics and structural alterations induced by this interaction, which has implications for reducing glioma cell chemosensitivity to therapeutic drugs.

We analyzed the effects of co-treating OSCC cells with small molecules targeting MPS-1 (BAY1217389), Aurora-B (Barasertib), or KSP (Ispinesib), alongside Cetuximab. Additionally, we examined EGFR, MPS-1, Aurora-B, and KSP expression in OSCC patient samples, revealing their clinicopathologic significance. This combinatorial approach suggests a promising strategy to improve treatment outcomes in OSCC.

We demonstrated that Paclitaxel (microtubule stabilizer), Palbociclib (cyclin dependent kinase 4/6 inhibitor), AZD1152 and GSK1070916 (aurora kinase B inhibitors) have anti-cancer functions beyond arresting cell cycle. We observed a trend that Paclitaxel suppressed STINGWT HCC more effectively than STINGKO HCC, suggesting that STING might contribute to the anti-tumor effects of Paclitaxel. Our study revealed the immune-mediated tumor-suppressing properties of cell cycle inhibitors and suggested combined treatment with immunotherapy as a potential therapeutic approach.

The combination of AZD1152 at IC50 concentrations together with ionizing radiation further reduced colony formation as compared to the single agent treatment. Our data support the notion that inhibition of the AURKB pathway is a promising strategy for treatment and radiosensitization of TNBC and warrants further translational studies.

Here, we investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic Navitoclax in oral cancer cells treated with the selective KSP inhibitor, Ispinesib, or AurB inhibitor, Barasertib, aiming to potentiate cell death. A mechanistic analysis underlying this synergistic activity, undertaken by live-cell imaging, is presented. Our data underscore the importance of combining BH3-mimetics with antimitotics in clinical trials to maximize their effectiveness.

Furthermore, it was showed that the inhibitor specific for AURKB (AZD1152) can suppress CCNE1 expression in CRC cells and inhibit tumor cell growth. To conclude, this research demonstrates that AURKB accelerated the tumorigenesis of CRC through its potential to epigenetically activate CCNE1 expression, suggesting AURKB as a promising therapeutic target in CRC.