Targeting N-Myc in Neuroblastoma with Selective Aurora Kinase A Degraders
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Le résumé fourni par la source
Summary Paragraph MYCN amplification is the most frequent genetic driver in high-risk neuroblastoma (NB) and strongly associated with poor prognosis. 1,2 The N-Myc transcription factor, which is encoded by MYCN , is a mechanistically validated, yet challenging target for NB therapy development. 3,4 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. 5,6 Allosteric Aurora-A inhibitors that displace N-Myc from binding can promote N-Myc degradation, but with limited efficacy. 7–10 Here, we report a chemical approach to decrease N-Myc levels through the targeted protein degradation of Aurora-A. A first-in-class Aurora-A/N-Myc degrader, HLB-0532259 (compound 4 ), was developed from a novel Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of both Aurora-A and N-Myc with nanomolar potency and excellent selectivity and surpasses the cellular efficacy of established allosteric Aurora-A inhibitors. HLB-0532259 exhibits favorable pharmacokinetics properties and elicits tumor reduction in murine xenograft NB models. More broadly, this study delineates a novel strategy for targeting “undruggable” proteins that are reliant on accessory proteins for cellular stabilization.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Targeting N-Myc in Neuroblastoma with Selective Aurora Kinase A Degraders
- Date Crossref
- 10/04/2022
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Minnesota Department of Medicinal Chemistry pays non établi dans la noticeUniversité ou école supérieure
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University of California San Diego Department of Chemistry and Biochemistry pays non établi dans la noticeUniversité ou école supérieure
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Stowers Institute for Medical Research pays non établi dans la noticeOrganisation à but non lucratif
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Howard Hughes Medical Institute pays non établi dans la noticeStructure de recherche
Department of Medicinal Chemistry — University of Minnesota, Department of Chemistry and Biochemistry — University of California San Diego et Stowers Institute for Medical Research, avec 1 autre affiliation.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.