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Article Dans Une Revue International Journal of Molecular Sciences Année : 2020

Dual-inhibitors of n-myc and aurka as potential therapy for neuroendocrine prostate cancer

Résumé

Resistance to androgen-receptor (AR) directed therapies is, among other factors, associated with Myc transcription factors that are involved in development and progression of many cancers. Overexpression of N-Myc protein in prostate cancer (PCa) leads to its transformation to advanced neuroendocrine prostate cancer (NEPC) that currently has no approved treatments. N-Myc has a short half-life but acts as an NEPC stimulator when it is stabilized by forming a protective complex with Aurora A kinase (AURKA). Therefore, dual-inhibition of N-Myc and AURKA would be an attractive therapeutic avenue for NEPC. Following our computer-aided drug discovery approach, compounds exhibiting potent N-Myc specific inhibition and strong anti-proliferative activity against several N-Myc driven cell lines, were identified. Thereafter, we have developed dual inhibitors of N-Myc and AURKA through structure-based drug design approach by merging our novel N-Myc specific chemical scaffolds with fragments of known AURKA inhibitors. Favorable binding modes of the designed compounds to both N-Myc and AURKA target sites have been predicted by docking. A promising lead compound, 70812, demonstrated low-micromolar potency against both N-Myc and AURKA in vitro assays and effectively suppressed NEPC cell growth.
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hal-03944772 , version 1 (18-01-2023)

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Anh-Tien Ton, Priyanka Singh, Helene Morin, Fuqiang Ban, Eric Leblanc, et al.. Dual-inhibitors of n-myc and aurka as potential therapy for neuroendocrine prostate cancer. International Journal of Molecular Sciences, 2020, International Journal of Molecular Sciences, 21 (21), pp.8277. ⟨10.3390/ijms21218277⟩. ⟨hal-03944772⟩

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