Targeting N-Myc with Selective Aurora Kinase A Degraders for Neuroblastoma Therapy
Abstract
The proposed project aims to develop a therapeutic regimen for the treatment of neuroblastoma. Therefore, this work is fully responsive to Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Area Neuroblastoma. Children with neuroblastoma would significantly benefit from a new treatment regimen. Therefore, this project is fully responsive to Military Health Focus Area Mission Readiness: Gaps in cancer prevention, early detection/diagnosis, prognosis, and/or treatment that may impact mission readiness and the health and well-being of military members, Veterans, their beneficiaries, and the general public.” Neuroblastoma remains the most common cancer in infants and the third most common childhood cancer. Although low- or moderate-risk neuroblastoma patients generally have a favorable outcome (80%-95% 5-year survival rates) with the current standard of care, approximately 50% of high-risk patients survive less than 5 years. One strong indicator (biomarker) of the aggressiveness of neuroblastoma is MYCN amplification, which is present in about half of high-risk neuroblastoma patients and remains the best characterized biomarker of poor prognosis. However, N-Myc, the protein product to MYCN, is a highly challenging target for drug discovery scientists and there are no N-Myc-targeted therapies currently available. N-Myc is a short-lived protein in normal cells and its cellular concentration is tightly controlled by rapid degradation. However, in aggressive neuroblastomas where high levels of N-Myc are observed, a second protein, Aurora kinase A (Aurora-A), stabilizes N-Myc and prevents its degradation. Other work has validated that blocking Aurora-A binding to NMyc can result in the degradation or loss of N-Myc, thereby yielding antiproliferative effects to cancer cells. Unfortunately, the existing drugs that block Aurora-A binding to N-Myc are largely ineffective in more aggressive neuroblastomas where N-Myc protein levels are high. We propose an innovative chemical approach to deplete N-Myc through the induced degradation of Aurora-A. This strategy is distinct from previous efforts (that have limited clinical utility) that block Aurora-A binding to N-Myc. We hypothesize that once Aurora-A is degraded, the unbound N-Myc, even at high expression levels, will be rapidly eliminated through its native degradation pathway. In our preliminary studies, we developed a series of first-in-class Aurora-A degraders and validated their potency of downregulating N-Myc protein levels in MYCN-amplified neuroblastoma cells. In this proposal, we will continue our efforts to further evaluate the lead compound, HLB-0533259, in more advanced cellular and mouse xenograft models to elucidate its selectivity, mechanism, and in vivo anti-neuroblastoma efficacy. We also propose to leverage medicinal chemistry, computational biology, and biophysical, biochemical, and cellular assays to develop Aurora-A degraders that are more potent and selective. The near-term goal of this project is to develop a potent Aurora-A degrader that is suitable for a clinical trial in neuroblastoma patients. The estimated time for advancing the first Aurora-A degrader into clinical trials is approximately 2-3 years following conclusion of this project, which is the amount of time needed for the extensive chemistry and safety validations that are required steps in the drug development process once a clinical candidate is identified. The long-term, ultimate applicability of this research is approval of a novel Aurora-A-degrading drug that improves survival rates and quality of life for children with high-risk neuroblastomas characterized by MYCN amplification. For neuroblastoma patients with MYCN amplification that receive the current standard-of-care therapy, the severe side effects and long course of treatment causes emotional and financial stress to parents and family. As such, parents and family members of children battling neuroblastoma that are active-duty
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110674
Entities
People
- Daniel A Harki
Organizations
- United States Army
- University of Minnesota