Exquisitely Specific anti-KRAS Biodegraders Inform on the Cellular Prevalence of Nucleotide-Loaded States
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High Resolution Image Download MS PowerPoint Slide Mutations to RAS proteins (H-, N-, and K-RAS) are among the most common oncogenic drivers, and tumors harboring these lesions are some of the most difficult to treat. Although covalent small molecules against KRAS G12C have shown promising efficacy against lung cancers, traditional barriers remain for drugging the more prevalent KRAS G12D and KRAS G12V mutants. Targeted degradation has emerged as an attractive alternative approach, but for KRAS, identification of the required high-affinity ligands continues to be a challenge. Another significant hurdle is the discovery of a hybrid molecule that appends an E3 ligase-recruiting moiety in a manner that satisfies the precise geometries required for productive polyubiquitin transfer while maintaining favorable druglike properties. To gain insights into the advantages and feasibility of KRAS targeted degradation, we applied a protein-based degrader (biodegrader) approach. This workflow centers on the intracellular expression of a chimeric protein consisting of a high-affinity target-binding domain fused to an engineered E3 ligase adapter. A series of anti-RAS biodegraders spanning different RAS isoform/nucleotide-state specificities and leveraging different E3 ligases provided definitive evidence for RAS degradability. Further, these established that the functional consequences of KRAS degradation are context dependent. Of broader significance, using the exquisite degradation specificity that biodegraders can possess, we demonstrated how this technology can be applied to answer questions that other approaches cannot. Specifically, application of the GDP-state specific degrader uncovered the relative prevalence of the “off-state” of WT and various KRAS mutants in the cellular context. Finally, if delivery challenges can be addressed, anti-RAS biodegraders will be exciting candidates for clinical development.
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Pan-KRAS and other mutant-specific KRAS degraders are in preclinical development.
“Similarly designed pan-KRAS188 and other mutant-specific KRAS degraders189 are in preclinical development.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [189]
This construct rapidly degraded PCNA and maintained low levels of PCNA for the 10 days of doxycycline dosing.
“This construct rapidly degraded PCNA and maintained low levels of PCNA for the 10 days of doxycycline dosing.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [219]
After demonstrating that their GFP-degrading bioPROTACs also degraded a GFP-tagged PCNA, Partridge and colleagues replaced the GFP-binding domain in one of those bioPROTACs with the 16-amino-acid Con1 peptide to generate a Con1-SPOP bioPROTAC.
“For example, after demonstrating that their GFP-degrading bioPROTACs also degraded a GFP-tagged proliferating cell nuclear antigen (PCNA), Partridge and colleagues219 replaced the GFP-binding domain in one of those bioPROTACs with the 16-amino-acid Con1 peptide, which contains the conserved PIP sequence common to PCNA binding partners, to generate a Con1–SPOP bioPROTAC.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [219]
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- Authors
- Lim, S., Khoo, R., Juang, Y.-C., Gopal, P., Zhang, H., Yeo, C., Peh, K. M., Teo, J., Ng, S., Henry, B., & Partridge, A. W.
- Affiliations
- MSD (Singapore) (SG)
- Corresponding author
- Partridge, Anthony W.
- Venue
- ACS Central Science
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-12-28
- Volume
- 7
- Issue
- 2
- Pages
- 274-291
- ISSN
- 2374-7943 (ISSN-L)
- 2374-7951
- PMC
- PMC7908030
- OpenAlex
- W3117806362
- Cited by
- 80
- References
- 72
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 16 · 2023: 15 · 2022: 15 · 2021: 9
- FWCI
- 3.16
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- ACS Central Science (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Merck
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- KRAS, targeted protein degradation, GDP-bound KRAS, E3 ubiquitin ligase, fusion protein, oncogenic Ras mutations
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