Breaking Down to Build Back Up: Aurora-A Degraders as Treatment for Neuroblastoma
The survival rate for nearly half of children diagnosed with high-risk neuroblastoma remains tragically low. This devastating outcome is often linked to the amplification of the MYCN gene (1). The N-Myc protein is normally short-lived (2), but in MYCN-amplified neuroblastoma cells, its stability is increased through binding with Aurora kinase A (Aurora-A), which prevents its degradation (3). To combat this, Daniel Harki, recipient of two AACR-Bayer Innovation and Discovery (IND) Grants, and his team have developed a new therapeutic strategy: targeted protein degradation of Aurora-A to indirectly reduce N-Myc levels (4). This approach circumvents the challenge of directly targeting the “undruggable” N-Myc protein.
The AACR-Bayer IND Grants encourage innovation and the translation of ideas from basic research into novel drugs. Dr. Harki, now a professor of medicinal chemistry at the University of Minnesota, received his second AACR-Bayer IND Grant in 2021 to advance the chemical optimization of Aurora-A-degrading compounds to enhance their potency, selectivity, and drug-like properties.
Leveraging PROteolysis-TArgeting Chimera (PROTAC) technology, Dr. Harki’s team engineered a selective and potent Aurora-A degrader, HLB-0532259, starting from the known CDK4/6 inhibitor ribociclib. This novel molecule was designed with an Aurora-A binding ligand that engages the Aurora-A/N-Myc complex. In a comprehensive screen against 468 kinases, HLB-0532259 demonstrated exceptional target selectivity, minimizing potential off-target effects. Treating MYCN-amplified neuroblastoma (NB) cells with HLB-0532259 induced rapid and potent degradation not only of Aurora-A but also of N-Myc. Notably, substantial reduction of N-Myc levels was observed only after a significant (over 75%) depletion of Aurora-A.
HLB-0532259 exhibited significant cytotoxicity against MYCN-amplified NB cells. In stark contrast, HLB-0532259 was much less effective against the MYCN-non-amplified NB cell line SK-N-AS, which is known to be resistant to Aurora-A knockdown. Supporting the importance of Aurora-A degradation, an inactive analog of HLB-0532259, which retains the ability to bind to and inhibit Aurora-A but lacks the PROTAC-mediated degradation mechanism, exhibited considerably lower cytotoxicity and induced less apoptosis in MYCN-amplified NB cells compared to HLB-0532259.
In vivo studies demonstrated that HLB-0532259 substantially impeded the growth of MYCN-amplified NB tumors in nude mice. Notably, after just nine days, a dosing regimen of HLB-0532259 every three days led to reduced mean tumor volume of 50.8 mm3 compared to the tumors in the vehicle group (374.4 mm3). This provides strong validation for the therapeutic potential of Aurora-A degradation. However, longer-term exposure revealed a critical challenge, with signs of intestinal necrosis observed, indicating a need to refine the compound’s properties. Despite this toxicity, Dr. Harki emphasized that these results represent an “exciting proof-of-concept for treating N-Myc-high pediatric neuroblastomas,” and his team is actively engaged in “optimizing their first-generation compound to improve its safety and efficacy, with promising next-generation analogues already showing remarkable potency in NB cell culture.”
Dr. Harki highlighted the crucial role of the AACR-Bayer Innovation and Discovery Grant, emphasizing that it “provided essential resources that helped him get the project off the ground.” Underscoring the difficulty of the therapeutic challenge, Dr. Harki stated that “the biggest impact of our work is validation that Aurora kinase A-targeted degraders can be developed to treat N-Myc-driven neuroblastomas.” Concluding with enthusiasm about the future, he shared, “We are very excited about the translational potential of this strategy for targeting pediatric neuroblastomas.”
References:
- Bagatell R, DuBois SG, Naranjo A, Belle J, Goldsmith KC, Park JR, et al. Children’s Oncology Group’s 2023 Blueprint for Research: Neuroblastoma. Pediatr Blood Cancer. 2023; 70(Suppl 6):e30572
- Beltran H. The N-Myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential. Mol Cancer Res. 2014; 12(6): 815–822
- Otto T, Horn S, Brockmann M, Eilers U, Schüttrumpf L, Popov N, et al. Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell. 2009; 15(1):67-78
- Tang J, Moorthy R, Hirsch LE, Demir O, Baker ZD, Naumann JA, et al. Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders. Cell Chemical Biology. 2025; 32(2):352-362