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  3. Targeted AURKA degradation: Towards new therapeutic agents for neuroblastoma

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

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: Serge.VanCalenbergh@UGent.be.
  • 6 Department of Biomolecular Medicine, Faculty of Medicine & Health Sciences, Ghent University, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium. Electronic address: Kaat.Durinck@UGent.be.
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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