Dataset Information

Targeted AURKA degradation: Towards new therapeutic agents for neuroblastoma

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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell

SUBMITTER: Teresa Mendes Maia

LAB HEAD: Kaat Durinck

PROVIDER: PXD040389 | Pride | 2023-02-27

REPOSITORIES: Pride

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Publications

Targeted AURKA degradation: Towards new therapeutic agents for neuroblastoma.

Rishfi Muhammad M Krols Simon S Martens Fien F Bekaert Sarah-Lee SL Sanders Ellen E Eggermont Aline A De Vloed Fanny F Goulding Joshua Robert JR Risseeuw Martijn M Molenaar Jan J De Wilde Bram B Van Calenbergh Serge S Durinck Kaat K

European journal of medicinal chemistry 20221218

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 (DC<sub>50,24h</sub> 3.9 nM, D<sub>max,24h</sub ...[more]

PMID: 36549117

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Dataset Information

Targeted AURKA degradation: Towards new therapeutic agents for neuroblastoma

Publications

Targeted AURKA degradation: Towards new therapeutic agents for neuroblastoma.

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