Targeted AURKA degradation: Towards new therapeutic agents for neuroblastoma

Muhammad Rishfi, Simon Krols, Fien Martens, Sarah-Lee Bekaert, Ellen Sanders, Aline Eggermont, Fanny De Vloed, Joshua Robert Goulding, Martijn Risseeuw, Jan Molenaar, Bram De Wilde, Serge Van Calenbergh, Kaat Durinck

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review


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.

Originele taal-2Engels
Pagina's (van-tot)115033
TijdschriftEuropean journal of medicinal chemistry
StatusE-publicatie vóór gedrukte publicatie - 18 dec. 2022
Extern gepubliceerdJa


Duik in de onderzoeksthema's van 'Targeted AURKA degradation: Towards new therapeutic agents for neuroblastoma'. Samen vormen ze een unieke vingerafdruk.

Citeer dit