Projects per year
Description
Despite the high prevalence of cancers driven by KRAS mutations, to date only the G12C mutation has been clinically proven to be druggable via covalent targeting of the mutated cysteine amino acid residue. However, in many cancer indications other KRAS mutations, such as G12D and -V, are far more prevalent and small molecule concepts that can address a wider variety of oncogenic KRAS alleles are in high clinical demand. Here we show that a single small molecule degrader can be used to simultaneously and potently target multiple KRAS alleles, including those not yet tractable by inhibitors. Degradation of oncogenic KRAS results in profound and sustained pathway modulation across a broad range of KRAS mutant cell lines. As a result, KRAS degraders inhibit growth of the majority of cancer cell lines driven by KRAS mutations while sparing models without genetic KRAS aberrations. Finally, we demonstrate that pharmacological degradation of oncogenic KRAS leads to tumour regression in vivo. Together, these findings unveil a new path towards addressing KRAS driven cancers with small molecule degraders. This experiment corresponds to Extended data Figure 3.f) graph in the manuscript
Date made available | 22 Oct 2024 |
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Publisher | ProteomeXchange |
Data Monitor categories
- Cancer
- degraders
- PROTAC
- KRAS
Projects
- 3 Finished
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Strategic Award: Wellcome Trust Technology Platform
Blow, J. (Investigator), Lamond, A. (Investigator) & Owen-Hughes, T. (Investigator)
1/01/13 → 30/09/18
Project: Research
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A Translational Engine for Biomedical Discoveries (Strategic Grant)
Fairlamb, A. (Investigator) & Gilbert, I. (Investigator)
1/01/13 → 30/09/15
Project: Research
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State-of-the-Art Facilities for Structural Biology at the University of Dundee
Hunter, B. (Investigator), Lilley, D. (Investigator), Owen-Hughes, T. (Investigator), Wyatt, P. (Investigator) & van Aalten, D. (Investigator)
1/03/12 → 28/02/17
Project: Research
Research output
- 1 Article
-
Targeting cancer with small molecule pan-KRAS degraders
Popow, J., Farnaby, W., Gollner, A., Kofink, C., Fischer, G., Wurm, M., Zollman, D., Wijaya, A., Mischerikow, N., Hasenoehrl, C., Prokofeva, P., Arnhof, H., Arce-Solano, S., Bell, S., Boeck, G., Diers, E., Frost, A. B., Goodwin-Tindall, J., Karolyi-Oezguer, J. & Khan, S. & 23 others, , 20 Sept 2024, In: Science. 385, 6715, p. 1338-1347 10 p.Research output: Contribution to journal › Article › peer-review
Open AccessFile1 Citation (Scopus)108 Downloads (Pure)