Journal Article

DKFZ-2023-00616

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Optimization of the Lead Compound NVP‐BHG712 as a Colorectal Cancer Inhibitor

Tröster, A. ; DiPrima, M. ; Jores, N. ; Kudlinzki, D.DKFZ* ; Sreeramulu, S. ; Gande, S. L.DKFZ* ; Linhard, V. ; Ludig, D. ; Schug, A. ; Saxena, K. ; Reinecke, M.DKFZ* ; Heinzlmeir, S. ; Leisegang, M. S. ; Wollenhaupt, J. ; Lennartz, F. ; Weiss, M. S. ; Kuster, B.DKFZ* ; Tosato, G. ; Schwalbe, H.DKFZ*

2023
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/chem.202203967

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 (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.

Note: 29(23):e202203967

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Frankfurt (FM01)
2. DKTK Koordinierungsstelle München (MU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

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Database coverage:
; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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