Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drugs
Abstract
The receptor tyrosine kinase EPHA2 (Ephrin type-A receptor 2) plays important roles in oncogenesis, metastasis, and treatment resistance, yet therapeutic targeting, drug discovery, or investigation of EPHA2 biology is hampered by the lack of appropriate inhibitors and structural information. Here, we used chemical proteomics to survey 235 clinical kinase inhibitors for their kinase selectivity and identified 24 drugs with submicromolar affinities for EPHA2. NMR-based conformational dynamics together with nine new cocrystal structures delineated drug-EPHA2 interactions in full detail. The combination of selectivity profiling, structure determination, and kinome wide sequence alignment allowed the development of a classification system in which amino acids in the drug binding site of EPHA2 are categorized into key, scaffold, potency, and selectivity residues. This scheme should be generally applicable in kinase drug discovery, and we anticipate that the provided information will greatly facilitate the development of selective EPHA2 inhibitors in particular and the repurposing of clinical kinase inhibitors in general.
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Crystal structures of foretinib in complex with c-Met, EphA2, and STK10 have been solved.
“Crystal structures of foretinib in complex with three different kinases have been solved to date (c-Met, EphA2, and STK10) 64, 65”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [65]
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Self-citationRationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta
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- Authors
- Heinzlmeir, S., Kudlinzki, D., Sreeramulu, S., Klaeger, S., Gande, S. L., Linhard, V., Wilhelm, M., Qiao, H., Helm, D., Ruprecht, B., Saxena, K., Médard, G., Schwalbe, H., & Kuster, B.
- Affiliations
- German Cancer Research Center (DE)
- Goethe University Frankfurt (DE)
- Technical University of Munich (DE)
- Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany
- Corresponding author
- Schwalbe, Harald
- ORCID
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-11-07
- Volume
- 11
- Issue
- 12
- Pages
- 3400-3411
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- OpenAlex
- W2535482197
- Cited by
- 56
- References
- 53
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 3 · 2023: 9 · 2022: 5 · 2021: 6 · 2020: 3 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 2
- FWCI
- 5.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- DESY Publication Database (PUBDB) (Deutsches Elektronen-Synchrotron) (submittedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- HZB Repository (Helmholtz-Zentrum Berlin für Materialien und Energie GmbH (HZB)) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- Deutsches Krebsforschungszentrum
- European Commission (N283570)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- EphA2, receptor tyrosine kinase, kinase inhibitors, drug repurposing, kinase selectivity profiling, co-crystal structure, kinase inhibitor discovery, carcinogenesis, metastasis, treatment resistance
- MeSH terms
- Amino Acid Sequence, Amino Acids, Clinical Trials as Topic, Humans, Ligands, Models, Molecular, Protein Binding, Receptor, EphA2, Proteomics, Cell Line, Tumor, Protein Kinase Inhibitors, Drug Discovery
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