MYCN amplification is the most frequent genetic driver in high-risk neuroblastoma (NB) and strongly associated with poor prognosis. The N-Myc transcription factor, which is encoded by MYCN, is a mechanistically validated, yet challenging target for 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. Allosteric Aurora-A inhibitors that displace N-Myc from binding can promote N-Myc degradation, but with limited efficacy. 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.
Overexpression of the MYCN proto-oncogene is one of the strongest biomarkers for poor prognosis in neuroblastoma patients. N-Myc, encoded by MYCN, is a highly attractive yet “undruggable” target in neuroblastoma drug discovery. N-Myc is a short-lived protein in normal neuronal progenitor cells; however, in MYCN-amplified neuroblastoma cells, overexpressed N-Myc is stabilized by high levels of Aurora kinase A (Aurora-A). Several Aurora-A allosteric modulators have been developed to disassociate N-Myc binding and promote its degradation. These compounds function through a competitive mechanism against N-Myc, and clinical trial results suggest limited efficacy in high-risk neuroblastoma patients where N-Myc is highly expressed. To develop Aurora-A modulators with greater effects in destabilizing N-Myc, targeted degradation of Aurora-A was investigated in this study. First, we developed a highly selective Aurora-A-binding ligand by chemically modifying ribociclib, which targets CDK4/6. Next, a series of potent Aurora-A/N-Myc degraders were developed using proteolysis targeting chimaera (PROTAC) technology. Our lead compound, HLB-0532259, was found to substantially decrease N-Myc levels in neuroblastoma cells following the degradation of Aurora-A with nanomolar potency. Mechanistic studies suggest that HLB-0532259 binds to Aurora-A in an uncompetitive manner with respect to N-Myc, which contributes to its high potency for degrading the Aurora-A/N-Myc pool. Mass spectrometry analysis demonstrates that HLB-0532259 possesses remarkable proteome-wide selectivity for Aurora-A and N-Myc degradation. Further studies have revealed that HLB-0532259 exhibits nanomolar cytotoxicities against a panel of MYCN-amplified neuroblastoma cells, good pharmacokinetic properties, and favorable therapeutic outcomes in a xenograft neuroblastoma mouse model. Taken together, our data strongly support HLB-0532259 as a promising lead compound for neuroblastoma therapy. Citation Format: Jian Tang, Ramkumar Moorthy, Ozlem Demir, Zachary D. Baker, Jordan A. Naumann, Katherine F. Jones, Michael J. Grillo, Ella Haefner, Ke Shi, Michaella J. Levy, Hideki Aihara, Reuben S. Harris, Rommie E. Amaro, Nicholas M. Levinson, Daniel A. Harki. Targeting N-Myc in neuroblastoma cells with selective Aurora kinase A degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2135.
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