Small Molecule N-myc Degraders as Novel Cancer Therapeutic Agents

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ABSTRACT The MYC family proteins are comprised of three paralogs termed Myc (c-myc), N-myc, and L-myc. The MYC proteins play a fundamental role in cell proliferation and oncogenesis by regulating cellular processes such as gene transcription, protein translation, cell cycle progression, and cell death. High levels of N-myc protein (gene name: MYCN) are often found in tumors of neuroendocrine origins, where it has been shown to drive tumor growth. Amplification of the MYCN locus occurs in approximately 50% of high-risk neuroblastoma, which is the most common extracranial solid malignancy of childhood. N-myc protein levels are highly regulated by Aurora kinase A: N-myc binds to Aurora kinase A to “escape” proteasomal degradation. The tool small molecule Aurora kinase A inhibitor, CD532, effectively dissociates N-myc from Aurora kinase A, resulting in N-myc protein destabilization 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, making it a poor drug candidate. To overcome these liabilities, we have developed distinct, novel small molecules, that effectively 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 vivo efficacy 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 a significant unmet need in patients.