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

Cell Chem Biol. 2025 Jan 6:S2451-9456(24)00516-6. doi: 10.1016/j.chembiol.2024.12.006. Online ahead of print.

Authors

Jian Tang¹, Ramkumar Moorthy¹, Laura E Hirsch¹, Özlem Demir², Zachary D Baker³, Jordan A Naumann⁴, Katherine F M Jones⁵, Michael J Grillo¹, Ella S Haefner¹, Ke Shi⁴, Michaella J Levy⁶, Harshita B Gupta⁷, Hideki Aihara⁴, Reuben S Harris⁸, Rommie E Amaro⁹, Nicholas M Levinson³, Daniel A Harki¹⁰

Affiliations

¹ Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
² Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
³ Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
⁴ Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
⁵ Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
⁶ KCAS Bioanalytical and Biomarker Services, Olathe, KS 66061, USA.
⁷ Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
⁸ Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, MN 55455, USA.
⁹ Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁰ Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: [email protected].

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

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.