N-Myc, encoded by the MYCN gene, belongs to the Myc family of transcription factors that are deregulated in a majority of cancers. In particular, N-Myc is a driver of central nervous system cancers such as neuroblastoma. The N-Myc oncoprotein lacks amenable pockets for small molecule binding and has been called “undruggable.” However, N-Myc can be targeted indirectly through its association with Aurora kinase A (AurA). N-Myc is rapidly degraded in healthy cells, but is stabilized by overexpressed AurA in MYCN-amplified neuroblastoma cells. In previous studies, our laboratory has developed the first-generation AurA/N-Myc degrader HLB-0532259 to indirectly decrease N-Myc protein levels in neuroblastoma cells. Using Proteolysis Targeting Chimera (PROTAC) technology, HLB-0532259 is a bifunctional molecule comprised of an AurA-targeting ligand tethered to an E3 ligase-recruiting moiety through a chemical linker. HLB-0532259 has demonstrated proximity-induced protein degradation of AurA and subsequent degradation of N-Myc. To further improve the degradation potency, specificity and physiochemical properties of HLB-0532259, we varied the linker length, composition, heteroatom placement, and rigidity of our lead compound. Our studies show that compounds with linkers containing sp-hybridized carbons are poorer degraders than their fully reduced counterparts, and compounds with linkers less than 7 atoms are weakly active. Our work resulted in the discovery of a further optimized compound, HLB-0535051, which has a 7-fold improvement in degradation efficiency (DC50) for both AurA and N-Myc, as well as a 3.5-fold improvement in cytotoxicity against the neuroblastoma cell line IMR-32. This poster highlights our efforts to optimize AurA/N-Myc degraders.

Structural optimization of chemical degraders for the aurora kinase A/N-Myc complex

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ACS Fall 2022

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