The MYC family proteins are comprised of three paralogs termed Myc (c-myc), N-myc, and L-myc. The MYCproteins play a fundamental role in cell proliferation and oncogenesis by regulating cellular processes such asgene transcription, protein translation, cell cycle progression, and cell death. High levels of N-myc protein (genename: MYCN) are often found in tumors of neuroendocrine origins, where it has been shown to drive tumorgrowth. Amplification of the MYCN locus occurs in approximately 50% of high-risk neuroblastoma, which is themost common extracranial solid malignancy of childhood. N-myc protein levels are highly regulated by Aurorakinase A: N-myc binds to Aurora kinase A to "escape" proteasomal degradation. The tool small molecule Aurorakinase A inhibitor, CD532, effectively dissociates N-myc from Aurora kinase A, resulting in N-myc proteindestabilization and regression of MYCN-amplified neuroblastomas. Although CD532 is an excellent proof-of-concept molecule, this compound has poor solubility, limited permeability, and poor metabolic stability, makingit a poor drug candidate. To overcome these liabilities, we have developed distinct, novel small molecules, thateffectively dissociate N-myc from Aurora A and destabilize N-myc and that are more bioavailable than CD532.For simplicity, these compounds are referred to as "N-myc degraders".The primary goal of our Phase I proposal is to improve the potency, selectivity, drug-like properties, and in vivoefficacy of our lead N-myc degrader, SSTA-152. We propose two specific aims:Specific Aim 1. Increase the potency and selectivity of SSTA-152.Specific Aim 2. Improve drug-like properties and in vivo efficacy of SSTA-152.The overall goal is to develop a clinical N-myc degrader for treating N-myc-driven cancers, which fulfills asignificant unmet need in patients.
Public Health Relevance Statement: PROJECT NARRATIVE
This proposal seeks to develop novel N-myc degraders to treat N-myc-driven cancers such as MYCN-amplified
neuroblastomas. Neuroblastoma is the most common extracranial solid malignancy of childhood, and
amplification of the MYCN locus is well-established as a biomarker for high-risk chemotherapy-refractory
neuroblastoma (30% - 40% long-term survival rate). Our preliminary results demonstrate that our N-myc
degraders are effective in inhibiting the growth of MYCN-amplified human neuroblastoma cells.
Project Terms: <21+ years old><20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome> | | | | | | | | | | | 