Pharmacological targeting of the pseudokinase Her3
Open accessAbstract
Her3 (also known as ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be 'undruggable' using ATP-competitive small molecules because it lacks appreciable kinase activity. Here we report what is to our knowledge the first selective Her3 ligand, TX1-85-1, that forms a covalent bond with Cys721 located in the ATP-binding site of Her3. We demonstrate that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3-dependent cancer cell lines. Subsequent derivatization with a hydrophobic adamantane moiety demonstrates that the resultant bivalent ligand (TX2-121-1) enhances inhibition of Her3-dependent signaling. Treatment of cells with TX2-121-1 results in partial degradation of Her3 and serendipitously interferes with productive heterodimerization between Her3 with either Her2 or c-Met. These results suggest that small molecules will be capable of perturbing the biological function of Her3 and ∼60 other pseudokinases found in human cells.
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Occupying the ATP binding pocket of HER3 is insufficient to functionally disrupt HER3.
“Consequently, occupying the, per se druggable, ATP binding pocket of HER3 has been shown to be insufficient to functionally disrupt HER3.11”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [11]
Targeted protein degraders, also known as PROTACs, are an emerging strategy for ablating previously undruggable protein functions.
“Targeted protein degraders, also known as PROTACs (PROteolysis TArgeting Chimeras), are an emerging strategy for ablating previously undruggable protein functions”
From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as Xie et al., 2014
Switching the HALO reactive linker with a high-affinity agonist for the androgen receptor, RU59063, or with an inhibitor against HER3, TX1-85-1, achieved similar degradation results.
“A similar result was achieved when the HALO reactive linker was switched with a high-affinity agonist for the androgen receptor, RU59063 [57], or with a newly developed inhibitor against the EGFR tyrosine kinase HER3, TX1-85-1 [61].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [61]
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- Authors
- Xie, T., Lim, S. M., Westover, K. D., Dodge, M. E., Ercan, D., Ficarro, S. B., Udayakumar, D., Gurbani, D., Tae, H. S., Riddle, S. M., Sim, T., Marto, J. A., Jänne, P. A., Crews, C. M., & Gray, N. S.
- Affiliations
- Harvard University (US)
- The University of Texas Southwestern Medical Center (US)
- Dana-Farber Cancer Institute (US)
- Yale University (US)
- Korean Association Of Science and Technology Studies (KR)
- Corresponding author
- Crews, Craig M
- Gray, Nathanael S
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2014-10-19
- Volume
- 10
- Issue
- 12
- Pages
- 1006-1012
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC4232461
- OpenAlex
- W1998944024
- Cited by
- 205
- References
- 52
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 15 · 2023: 17 · 2022: 23 · 2021: 21 · 2020: 18 · 2019: 18 · 2018: 16 · 2017: 24 · 2016: 11 · 2015: 13
- FWCI
- 7.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (P01CA154303)
- National Institute of Allergy and Infectious Diseases (AI 084140-03, R01AI084140)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- HER3, pseudokinase, covalent kinase inhibitors, protein degradation, receptor heterodimerization, HER2, c-Met, receptor tyrosine kinase signaling
- MeSH terms
- Acrylamides, Adamantane, Adenine, Adenosine Triphosphate, Antineoplastic Agents, Cysteine, Humans, Signal Transduction, Gene Expression Regulation, Neoplastic, Erb-b2 Receptor Tyrosine Kinases, Proto-Oncogene Proteins c-met, Catalytic Domain, Receptor, ErbB-3, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Protein Multimerization, Hydrophobic and Hydrophilic Interactions, Molecular Targeted Therapy, Proteolysis, Molecular Docking Simulation
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