Translation termination factor GSPT1 is a phenotypically relevant off-target of heterobifunctional phthalimide degraders
Abstract
Protein degradation is an emerging therapeutic strategy with a unique molecular pharmacology that enables the disruption of all functions associated with a target. This is particularly relevant for proteins depending on molecular scaffolding, such as transcription factors or receptor tyrosine kinases (RTKs). To address tractability of multiple RTKs for chemical degradation by the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4 CRBN ), we synthesized a series of phthalimide degraders based on the promiscuous kinase inhibitors sunitinib and PHA665752. While both series failed to induce degradation of their consensus targets, individual molecules displayed pronounced efficacy in leukemia cell lines. Orthogonal target identification supported by molecular docking led us to identify the translation termination factor G1 to S phase transition 1 (GSPT1) as a converging off-target, resulting from inadvertent E3 ligase modulation. This research highlights the importance of monitoring degradation events that are independent of the respective targeting ligand as a unique feature of small-molecule degraders.
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Possible off-target effects may arise from the E3 ligase ligand side, such as GSPT1 degradation.
“However, possible off-target effects may arise from the E3 ligase ligand side, such as the degradation of GSPT1 in this work and others[42–44].”
From Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries (2021) · cites this paper as [43]
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- Authors
- Ishoey, M., Chorn, S., Singh, N., Jaeger, M. G., Brand, M., Paulk, J., Bauer, S., Erb, M. A., Parapatics, K., Müller, A. C., Bennett, K. L., Ecker, G. F., Bradner, J. E., & Winter, G. E.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Austrian Academy of Sciences (AT)
- University of Vienna (AT)
- Corresponding author
- Bradner, James E.
- Winter, Georg E.
- ORCID
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-01-22
- Volume
- 13
- Issue
- 3
- Pages
- 553-560
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- OpenAlex
- W2785263247
- Cited by
- 177
- References
- 32
- Citations by year
- 2026: 10 · 2025: 22 · 2024: 24 · 2023: 27 · 2022: 25 · 2021: 24 · 2020: 25 · 2019: 12 · 2018: 6 · 2014: 1
- FWCI
- 6.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01-CA109901, R01-CA176745)
- Carlsbergfondet (CF15-0518)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- GSPT1, heterobifunctional degraders, E3 ubiquitin ligase, translation termination factor, sunitinib, PHA-665752, receptor tyrosine kinase, leukemia cell lines, molecular docking
- MeSH terms
- Humans, Peptide Chain Termination, Translational, Peptide Termination Factors, Phthalimides, Ubiquitin-Protein Ligases, Cell Line, Tumor, Protein Kinase Inhibitors, Proteolysis, Molecular Docking Simulation
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