Targeted Degradation of the Oncogenic Phosphatase SHP2
Open accessAbstract
SHP2 is a protein tyrosine phosphatase that plays a critical role in the full activation of the Ras-MAPK pathway upon stimulation of receptor tyrosine kinases, which are frequently amplified or mutationally activated in human cancer. In addition, activating mutations in SHP2 result in developmental disorders and hematologic malignancies. Several allosteric inhibitors have been developed for SHP2 and are currently in clinical trials. Here, we report the development and evaluation of a SHP2 PROTAC created by conjugating RMC-4550 with pomalidomide using a PEG linker. This molecule is highly selective for SHP2, induces degradation of SHP2 in leukemic cells at submicromolar concentrations, inhibits MAPK signaling, and suppresses cancer cell growth. SHP2 PROTACs serve as an alternative strategy for targeting ERK-dependent cancers and are useful tools alongside allosteric inhibitors for dissecting the mechanisms by which SHP2 exerts its oncogenic activity.
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R1-5C (207) employs pomalidomide as the ligand and is connected to RMC-4550 via a PEG linker, showcasing superior SHP2 degradation.
“Another degrader, R1-5C (207), employed pomalidomide as the ligand and connected it to RMC-4550 via a PEG linker, showcasing superior SHP2 degradation (Table 4).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [500]
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- Authors
- Vemulapalli, V., Donovan, K. A., Seegar, T. C. M., Rogers, J. M., Bae, M., Lumpkin, R. J., Cao, R., Henke, M. T., Ray, S. S., Fischer, E. S., Cuny, G. D., & Blacklow, S. C.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- University of Cincinnati (US)
- RA Capital, 200 Berkeley Street, Boston, Massachusetts 02116, United States
- University of Houston (US)
- Corresponding author
- Blacklow, Stephen C.
- ORCID
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-08-19
- Volume
- 60
- Issue
- 34
- Pages
- 2593-2609
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC8410664
- OpenAlex
- W3194350905
- Cited by
- 43
- References
- 34
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 9 · 2023: 8 · 2022: 11 · 2021: 1 · 2014: 1
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Biochemistry (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R35 CA220340)
- Harvard Medical School
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- 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
- Keywords
- SHP2, PROTACs, protein degradation, protein tyrosine phosphatase, RAS/MAPK pathway, pomalidomide, PEG linker, allosteric inhibitors, leukemia, MAPK signaling inhibition, tumor cell growth inhibition
- MeSH terms
- Methanol, Antineoplastic Agents, Humans, Mutation, Neoplasms, Pyrazines, Signal Transduction, Crystallography, X-Ray, Cell Line, Tumor, Cell Proliferation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Molecular Targeted Therapy, Proteolysis
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