Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders

Jian Tang; Ramkumar Moorthy; Laura E. Hirsch; Özlem Demir; Zachary D. Baker; Jordan A. Naumann; Katherine F.M. Jones; Michael J. Grillo; Ella S. Haefner; Ke Shi; Michaella J. Levy; Harshita B. Gupta; Hideki Aihara; Reuben S. Harris; Rommie E. Amaro; Nicholas M. Levinson; Daniel A. Harki

doi:10.1016/j.chembiol.2024.12.006

Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders

Jian Tang, Ramkumar Moorthy, Laura E. Hirsch, Özlem Demir, Zachary D. Baker, Jordan A. Naumann, Katherine F.M. Jones, Michael J. Grillo, Ella S. Haefner, Ke Shi, Michaella J. Levy, Harshita B. Gupta, Hideki Aihara, Reuben S. Harris, Rommie E. Amaro, Nicholas M. Levinson, Daniel A. Harki

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Abstract

The N-Myc transcription factor, encoded by MYCN, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in MYCN-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels. A potent Aurora-A degrader, HLB-0532259 (compound 4), was developed from an Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of Aurora-A, which elicits concomitant N-Myc degradation, with nanomolar potency and excellent selectivity. HLB-0532259 surpasses the cellular efficacy of established allosteric Aurora-A inhibitors, exhibits favorable pharmacokinetic properties, and elicits tumor reduction in a murine xenograft NB model. This study broadly delineates a strategy for targeting “undruggable” proteins that are reliant on accessory proteins for cellular stabilization.

Original language	English (US)
Pages (from-to)	352-362.e10
Journal	Cell Chemical Biology
Volume	32
Issue number	2
DOIs	https://doi.org/10.1016/j.chembiol.2024.12.006
State	Published - Feb 20 2025

Bibliographical note

Publisher Copyright:
© 2024 Elsevier Ltd

Keywords

Aurora kinase A
MYCN
N-Myc
PROTAC
TPD
neuroblastoma
targeted protein degradation
transcription factor

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2024.12.006

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Tang, J., Moorthy, R., Hirsch, L. E., Demir, Ö., Baker, Z. D., Naumann, J. A., Jones, K. F. M., Grillo, M. J., Haefner, E. S., Shi, K., Levy, M. J., Gupta, H. B., Aihara, H., Harris, R. S., Amaro, R. E., Levinson, N. M., & Harki, D. A. (2025). Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders. Cell Chemical Biology, 32(2), 352-362.e10. https://doi.org/10.1016/j.chembiol.2024.12.006

Tang, J, Moorthy, R, Hirsch, LE, Demir, Ö, Baker, ZD, Naumann, JA, Jones, KFM, Grillo, MJ, Haefner, ES, Shi, K, Levy, MJ, Gupta, HB, Aihara, H , Harris, RS, Amaro, RE, Levinson, NM & Harki, DA 2025, 'Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders', Cell Chemical Biology, vol. 32, no. 2, pp. 352-362.e10. https://doi.org/10.1016/j.chembiol.2024.12.006

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abstract = "The N-Myc transcription factor, encoded by MYCN, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in MYCN-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels. A potent Aurora-A degrader, HLB-0532259 (compound 4), was developed from an Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of Aurora-A, which elicits concomitant N-Myc degradation, with nanomolar potency and excellent selectivity. HLB-0532259 surpasses the cellular efficacy of established allosteric Aurora-A inhibitors, exhibits favorable pharmacokinetic properties, and elicits tumor reduction in a murine xenograft NB model. This study broadly delineates a strategy for targeting “undruggable” proteins that are reliant on accessory proteins for cellular stabilization.",

keywords = "Aurora kinase A, MYCN, N-Myc, PROTAC, TPD, neuroblastoma, targeted protein degradation, transcription factor",

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doi = "10.1016/j.chembiol.2024.12.006",

language = "English (US)",

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AU - Tang, Jian

AU - Moorthy, Ramkumar

AU - Hirsch, Laura E.

AU - Demir, Özlem

AU - Baker, Zachary D.

AU - Naumann, Jordan A.

AU - Jones, Katherine F.M.

AU - Grillo, Michael J.

AU - Haefner, Ella S.

AU - Shi, Ke

AU - Levy, Michaella J.

AU - Gupta, Harshita B.

AU - Aihara, Hideki

AU - Harris, Reuben S.

AU - Amaro, Rommie E.

AU - Levinson, Nicholas M.

AU - Harki, Daniel A.

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N2 - The N-Myc transcription factor, encoded by MYCN, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in MYCN-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels. A potent Aurora-A degrader, HLB-0532259 (compound 4), was developed from an Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of Aurora-A, which elicits concomitant N-Myc degradation, with nanomolar potency and excellent selectivity. HLB-0532259 surpasses the cellular efficacy of established allosteric Aurora-A inhibitors, exhibits favorable pharmacokinetic properties, and elicits tumor reduction in a murine xenograft NB model. This study broadly delineates a strategy for targeting “undruggable” proteins that are reliant on accessory proteins for cellular stabilization.

AB - The N-Myc transcription factor, encoded by MYCN, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in MYCN-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels. A potent Aurora-A degrader, HLB-0532259 (compound 4), was developed from an Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of Aurora-A, which elicits concomitant N-Myc degradation, with nanomolar potency and excellent selectivity. HLB-0532259 surpasses the cellular efficacy of established allosteric Aurora-A inhibitors, exhibits favorable pharmacokinetic properties, and elicits tumor reduction in a murine xenograft NB model. This study broadly delineates a strategy for targeting “undruggable” proteins that are reliant on accessory proteins for cellular stabilization.

KW - Aurora kinase A

KW - MYCN

KW - N-Myc

KW - PROTAC

KW - TPD

KW - neuroblastoma

KW - targeted protein degradation

KW - transcription factor

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ER -

Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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