8BOG

Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with Compound 7

Summary for 8BOG

• Entry DOI: 10.2210/pdb8bog/pdb
• Descriptor: Ephrin type-A receptor 2, ~{N}-[4-methyl-3-[(1-methyl-6-pyridin-3-yl-pyrazolo[3,4-d]pyrimidin-4-yl)amino]phenyl]-3-(trifluoromethyl)benzamide (3 entities in total)
• Functional Keywords: inhibitor, complex, protein tyrosine kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34966.32

Authors

Linhard, V.,Witt, K.,Gande, S.,Wollenhaupt, J.,Lennartz, F.,Weiss, M.S.,Schwalbe, H. (deposition date: 2022-11-15, release date: 2023-03-08, Last modification date: 2024-02-07)

Primary citation

Troster, A.,DiPrima, M.,Jores, N.,Kudlinzki, D.,Sreeramulu, S.,Gande, S.L.,Linhard, V.,Ludig, D.,Schug, A.,Saxena, K.,Reinecke, M.,Heinzlmeir, S.,Leisegang, M.S.,Wollenhaupt, J.,Lennartz, F.,Weiss, M.S.,Kuster, B.,Tosato, G.,Schwalbe, H.
Optimization of the Lead Compound NVP-BHG712 as a Colorectal Cancer Inhibitor.
Chemistry, 29:e202203967-e202203967, 2023

PubMed Abstract: The ephrin type-A receptor 2 (EPHA2) kinase belongs to the largest family of receptor tyrosine kinases. There are several indications of an involvement of EPHA2 in the development of infectious diseases and cancer. Despite pharmacological potential, EPHA2 is an under-examined target protein. In this study, we synthesized a series of derivatives of the inhibitor NVP-BHG712 and triazine-based compounds. These compounds were evaluated to determine their potential as kinase inhibitors of EPHA2, including elucidation of their binding mode (X-ray crystallography), affinity (microscale thermophoresis), and selectivity (Kinobeads assay). Eight inhibitors showed affinities in the low-nanomolar regime (K <10 nM). Testing in up to seven colon cancer cell lines that express EPHA2 reveals that several derivatives feature promising effects for the control of human colon carcinoma. Thus, we have developed a set of powerful tool compounds for fundamental new research on the interplay of EPH receptors in a cellular context.

PubMed: 36799129
DOI: 10.1002/chem.202203967

Experimental method

X-RAY DIFFRACTION (1.47 Å)