Dual-Inhibitors of N-Myc and AURKA As Potential Therapy for Neuroendocrine Prostate Cancer

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 Nov 10

PMID 33167327

Citations 12

Authors

Anh-Tien Ton

Kriti Singh

Helene Morin

Fuqiang Ban

Eric Leblanc

Joseph Lee

Nada Lallous

Artem Cherkasov

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Interactions between key genes and pathways in prostate cancer progression and therapy resistance.

Wu F, Zhang H, Hao M Front Oncol. 2025; 15:1467540.

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The role of Aurora kinase A in hepatocellular carcinoma: Unveiling the intriguing functions of a key but still underexplored factor in liver cancer.

Grisetti L, Garcia C, Saponaro A, Tiribelli C, Pascut D Cell Prolif. 2024; 57(8):e13641.

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Tissue-Based Diagnostic Biomarkers of Aggressive Variant Prostate Cancer: A Narrative Review.

Kouroukli O, Bravou V, Giannitsas K, Tzelepi V Cancers (Basel). 2024; 16(4).

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Targeting Key Players of Neuroendocrine Differentiation in Prostate Cancer.

Zamora I, Freeman M, Encio I, Rotinen M Int J Mol Sci. 2023; 24(18).

PMID: 37761978 PMC: 10531052. DOI: 10.3390/ijms241813673.

Lineage Plasticity and Stemness Phenotypes in Prostate Cancer: Harnessing the Power of Integrated "Omics" Approaches to Explore Measurable Metrics.

Logotheti S, Papadaki E, Zolota V, Logothetis C, Vrahatis A, Soundararajan R Cancers (Basel). 2023; 15(17).

PMID: 37686633 PMC: 10486655. DOI: 10.3390/cancers15174357.

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