2. Academic Validation
  3. Second-Generation AURKA-Targeting PROTACs: Structural Optimization toward in Vivo Degradation in Neuroblastoma

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

  • J Med Chem. 2025 Nov 27;68(22):23962-23976. doi: 10.1021/acs.jmedchem.5c01271.
Simon Krols 1 2,  Muhammad Rishfi 3 2,  Fien Martens 3 2,  Anouk Van Hauwermeiren 1 2,  Ellen Sanders 3 2,  Pieter-Jan De Sutter 4,  An Vermeulen 4,  Kaat De Wever 3 2,  Sarah-Lee Bekaert 3 2,  M Emmy M Dolman 5 6,  Gabor Tax 5 6,  Alvin Kamili 5 6,  Jamie I Fletcher 5 6,  Lisa Depestel 3 2,  Bram De Wilde 3 2 7,  Kaat Durinck 3 2,  Serge Van Calenbergh 1 2
Affiliations

Affiliations

  • 1 Laboratory of Medicinal Chemistry, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
  • 2 Cancer Research Institute Ghent, Corneel Heymanslaan 10, 9000 Ghent, Belgium.
  • 3 Pediatric Precision Oncology Lab, Department of Biomolecular Medicine, Faculty of Medicine & Health Sciences, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium.
  • 4 Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
  • 5 Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, Sydney, NSW 2052, Australia.
  • 6 School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Kensington, Sydney, NSW 2052, Australia.
  • 7 Department of Internal Medicine and Pediatrics, Faculty of Medicine & Health Sciences, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium.
PMID: 41252673 DOI: 10.1021/acs.jmedchem.5c01271
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.

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