Targeted AURKA degradation: Towards new therapeutic agents for neuroblastoma

  • Eur J Med Chem. 2023 Feb 5:247:115033. doi: 10.1016/j.ejmech.2022.115033.
Muhammad Rishfi  1 ,  Simon Krols  2 ,  Fien Martens  1 ,  Sarah-Lee Bekaert  1 ,  Ellen Sanders  1 ,  Aline Eggermont  1 ,  Fanny De Vloed  1 ,  Joshua Robert Goulding  1 ,  Martijn Risseeuw  2 ,  Jan Molenaar  3 ,  Bram De Wilde  4 ,  Serge Van Calenbergh  5 ,  Kaat Durinck  6
Affiliations
  • 1. Department of Biomolecular Medicine, Faculty of Medicine & Health Sciences, Ghent University, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
  • 2. Laboratory for medicinal chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
  • 3. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • 4. Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine & Health Sciences, Ghent University, Belgium.
  • 5. Laboratory for medicinal chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium. Electronic address: [email protected].
  • 6. Department of Biomolecular Medicine, Faculty of Medicine & Health Sciences, Ghent University, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium. Electronic address: [email protected].
PMID: 36549117 DOI: 10.1016/j.ejmech.2022.115033
Abstract

Aurora Kinase A (AURKA) is a well-established target in neuroblastoma (NB) due to both its catalytic functions during Mitosis and its kinase-independent functions, including stabilization of the key oncoprotein MYCN. We present a structure-activity relationship (SAR) study of MK-5108-derived PROTACs against AURKA by exploring different linker lengths and exit vectors on the thalidomide moiety. PROTAC SK2188 induces the most potent AURKA degradation (DC50,24h 3.9 nM, Dmax,24h 89%) and shows an excellent binding and degradation selectivity profile. Treatment of NGP neuroblastoma cells with SK2188 induced concomitant MYCN degradation, high replication stress/DNA damage levels and Apoptosis. Moreover, SK2188 significantly outperforms the parent inhibitor MK-5108 in a cell proliferation screen and patient-derived organoids. Furthermore, altering the attachment point of the PEG linker to the 5-position of thalidomide allowed us to identify a potent AURKA degrader with a linker as short as 2 PEG units. With this, our SAR-study provides interesting lead structures for further optimization and validation of AURKA degradation as a potential therapeutic strategy in neuroblastoma.

Keywords
AURKA; MYCN; Neuroblastoma; PROTAC; Targeted protein degradation.
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