Targeted AURKA degradation : towards new therapeutic agents for neuroblastoma
- Author
- Muhammad Rishfi (UGent) , Simon Krols (UGent) , Fien Martens (UGent) , Sarah-Lee Bekaert (UGent) , Ellen Sanders (UGent) , Aline Eggermont (UGent) , Fanny De Vloed (UGent) , Joshua Robert Goulding (UGent) , Martijn Risseeuw (UGent) , Jan Molenaar, Bram De Wilde (UGent) , Serge Van Calenbergh (UGent) and Kaat Durinck (UGent)
- Organization
- Project
- 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
- Organic Chemistry, Drug Discovery, Medicinal chemistry, Targeted protein degradation, MYCN, PROTAC, Neuroblastoma, AURKA
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01GNSE8MH73F7HMJAPDFRCPBNS
- MLA
- Rishfi, Muhammad, et al. “Targeted AURKA Degradation : Towards New Therapeutic Agents for Neuroblastoma.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 247, Elsevier BV, 2023, doi:10.1016/j.ejmech.2022.115033.
- APA
- Rishfi, M., Krols, S., Martens, F., Bekaert, S.-L., Sanders, E., Eggermont, A., … Durinck, K. (2023). Targeted AURKA degradation : towards new therapeutic agents for neuroblastoma. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 247. https://doi.org/10.1016/j.ejmech.2022.115033
- Chicago author-date
- Rishfi, Muhammad, Simon Krols, Fien Martens, Sarah-Lee Bekaert, Ellen Sanders, Aline Eggermont, Fanny De Vloed, et al. 2023. “Targeted AURKA Degradation : Towards New Therapeutic Agents for Neuroblastoma.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 247. https://doi.org/10.1016/j.ejmech.2022.115033.
- Chicago author-date (all authors)
- Rishfi, Muhammad, 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, and Kaat Durinck. 2023. “Targeted AURKA Degradation : Towards New Therapeutic Agents for Neuroblastoma.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 247. doi:10.1016/j.ejmech.2022.115033.
- Vancouver
- 1.Rishfi M, Krols S, Martens F, Bekaert S-L, Sanders E, Eggermont A, et al. Targeted AURKA degradation : towards new therapeutic agents for neuroblastoma. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. 2023;247.
- IEEE
- [1]M. Rishfi et al., “Targeted AURKA degradation : towards new therapeutic agents for neuroblastoma,” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 247, 2023.
@article{01GNSE8MH73F7HMJAPDFRCPBNS,
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.}},
articleno = {{115033}},
author = {{Rishfi, Muhammad and Krols, Simon and Martens, Fien and Bekaert, Sarah-Lee and Sanders, Ellen and Eggermont, Aline and De Vloed, Fanny and Goulding, Joshua Robert and Risseeuw, Martijn and Molenaar, Jan and De Wilde, Bram and Van Calenbergh, Serge and Durinck, Kaat}},
issn = {{0223-5234}},
journal = {{EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY}},
keywords = {{Organic Chemistry,Drug Discovery,Medicinal chemistry,Targeted protein degradation,MYCN,PROTAC,Neuroblastoma,AURKA}},
language = {{eng}},
pages = {{14}},
publisher = {{Elsevier BV}},
title = {{Targeted AURKA degradation : towards new therapeutic agents for neuroblastoma}},
url = {{http://dx.doi.org/10.1016/j.ejmech.2022.115033}},
volume = {{247}},
year = {{2023}},
}
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