9BZL

Targeting N-Myc in Neuroblastoma with Selective Aurora Kinase A Degraders

9BZL の概要

• エントリーDOI: 10.2210/pdb9bzl/pdb
• 分子名称: Aurora kinase A, 7-cyclopentyl-N,N-dimethyl-2-{[5-(methylcarbamoyl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (3 entities in total)
• 機能のキーワード: aurora a kinase, aura kinase, n-myc degrader, aura inhibitor, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33388.11

構造登録者

Baker, Z.D.,Tang, J.,Shi, K.,Aihara, H.,Levinson, N.M.,Harki, D.A. (登録日: 2024-05-24, 公開日: 2025-01-15, 最終更新日: 2025-03-05)

主引用文献

Tang, J.,Moorthy, R.,Hirsch, L.E.,Demir, O.,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.
Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders.
Cell Chem Biol, 32:352-, 2025

PubMed 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.

PubMed: 39778578
DOI: 10.1016/j.chembiol.2024.12.006

実験手法

X-RAY DIFFRACTION (1.81 Å)