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Optimization of the Lead Compound NVP-BHG712 as a Colorectal Cancer Inhibitor

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 (KD <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.

 

Comments:

It seems like you're describing a research study that explores the potential of EPHA2 kinase inhibitors in the context of infectious diseases and cancer, particularly focusing on colon carcinoma. The study involves the synthesis of specific compounds, their evaluation as kinase inhibitors for EPHA2, and subsequent testing in colon cancer cell lines expressing EPHA2. The results indicate that several derivatives of the inhibitors show promising effects in controlling human colon carcinoma.

This research is significant because EPHA2, being a member of the receptor tyrosine kinase family, is implicated in various diseases, including infectious diseases and cancer. Despite its pharmacological potential, EPHA2 has been underexplored as a target for therapeutic intervention. By synthesizing and testing specific inhibitors, the study aims to shed light on the role of EPHA2 and its inhibitors in disease development and potential treatment strategies. The findings also provide valuable tool compounds for further research on the interactions of EPH receptors in cellular contexts.