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

被引：0
|
作者：
Tang, Jian [1 ]
Moorthy, Ramkumar [1 ,2 ]
Hirsch, Laura E. [1 ]
Demir, Ozlem
Baker, Zachary D. [3 ]
Naumann, Jordan A. [4 ]
Jones, Katherine F. M. [5 ]
Grillo, Michael J. [1 ]
Haefner, Ella S. [1 ]
Shi, Ke [4 ]
Levy, Michaella J. [6 ]
Gupta, Harshita B.
Aihara, Hideki [4 ]
Harris, Reuben S. [7 ,8 ]
Amaro, Rommie E. [9 ]
Levinson, Nicholas M.
Harki, Daniel A. [1 ,4 ,5 ]
机构：
[1] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA
[2] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
[3] Univ Minnesota, Dept Pharmacol, Minneapolis, MN 55455 USA
[4] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA
[5] Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA
[6] KCAS Bioanalyt & Biomarker Serv, Olathe, KS 66061 USA
[7] Univ Texas Hlth San Antonio, Dept Biochem & Struct Biol, San Antonio, TX 78229 USA
[8] Univ Minnesota, Howard Hughes Med Inst, Minneapolis, MN 55455 USA
[9] Univ Calif San Diego, Dept Mol Biol, La Jolla, CA 92093 USA
来源：
CELL CHEMICAL BIOLOGY | 2025年 / 32卷 / 02期
基金：
美国国家科学基金会; 美国国家卫生研究院;
关键词：
E3 UBIQUITIN LIGASE; RIBOSOME BIOGENESIS; INHIBITION; DESTABILIZATION; STABILIZATION; DEGRADATION; COMPLEX; BINDING;
D O I：
10.1016/j.chembiol.2024.12.006
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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.
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页数：22
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