J Med Chem. 2025 Nov 18. doi: 10.1021/acs.jmedchem.5c01271. Online ahead of print.
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 degrader efficiently reduced AURKA levels in vivo in a neuroblastoma xenograft mouse model. Moreover, MDR1-mediated PROTAC efflux was identified as a key intrinsic mechanism limiting in vitro potency. These results establish SK4454 and SK5527 as advanced AURKA degraders with improved pharmacokinetic properties, warranting further preclinical evaluation.
PMID:41252673 | DOI:10.1021/acs.jmedchem.5c01271
