Second-Generation AURKA-Targeting PROTACs: Structural Optimization toward in Vivo Degradation in Neuroblastoma.

ABSTRACT: Aurora kinase A (AURKA) is an established oncogenic factor and therapeutic target in neuroblastoma due to its roles in mitosis and stability of the MYCN protein. We previously identified SK2188 as a highly potent, selective, and fast-acting AURKA degrader capable of inducing MYCN destabilization. However, SK2188 showed low systemic exposure and rapid clearance in mice, necessitating further chemical optimization. Here, we describe our structure-activity optimization efforts involving linker rigidification and incorporation of alternative cereblon- and AURKA-recruiting ligands, leading to two optimized PROTACs, SK4454 and SK5527. Both compounds retained rapid and selective AURKA degradation with improved pharmacokinetic properties. Importantly, single intravenous administration of either de

SUBMITTER: Krols S 

PROVIDER: S-EPMC12670405 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature