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

Alix Tröster; Michael DiPrima; Nathalie Jores; Denis Kudlinzki; Sridhar Sreeramulu; Santosh L. Gande; Verena Linhard; Damian Ludig; Alexander Schug; Krishna Saxena; Maria Reinecke; Stephanie Heinzlmeir; Matthias S. Leisegang; Jan Wollenhaupt; Frank Lennartz; Manfred S. Weiss; Bernhard Kuster; Giovanna Tosato; Harald Schwalbe

doi:10.1002/chem.202203967

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

Alix Tröster, Michael DiPrima, Nathalie Jores, Denis Kudlinzki, Sridhar Sreeramulu, Santosh L. Gande, Verena Linhard, Damian Ludig, Alexander Schug, Krishna Saxena, Maria Reinecke, Stephanie Heinzlmeir, Matthias S. Leisegang, Jan Wollenhaupt, Frank Lennartz, Manfred S. Weiss, Bernhard Kuster, Giovanna Tosato, Harald Schwalbe

Chair of Bioanalytics

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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_D<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.

Original language	English
Article number	e202203967
Journal	Chemistry - A European Journal
Volume	29
Issue number	23
DOIs	https://doi.org/10.1002/chem.202203967
State	Published - 21 Apr 2023

Keywords

EPH receptors
colorectal cancer
drug discovery
medicinal chemistry
structural biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/chem.202203967

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Tröster, 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. (2023). Optimization of the Lead Compound NVP-BHG712 as a Colorectal Cancer Inhibitor. Chemistry - A European Journal, 29(23), Article e202203967. https://doi.org/10.1002/chem.202203967

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title = "Optimization of the Lead Compound NVP-BHG712 as a Colorectal Cancer Inhibitor",

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.",

keywords = "EPH receptors, colorectal cancer, drug discovery, medicinal chemistry, structural biology",

author = "Alix Tr{\"o}ster and Michael DiPrima and Nathalie Jores and Denis Kudlinzki and Sridhar Sreeramulu and Gande, {Santosh L.} and Verena Linhard and Damian Ludig and Alexander Schug and Krishna Saxena and Maria Reinecke and Stephanie Heinzlmeir and Leisegang, {Matthias S.} and Jan Wollenhaupt and Frank Lennartz and Weiss, {Manfred S.} and Bernhard Kuster and Giovanna Tosato and Harald Schwalbe",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.",

year = "2023",

month = apr,

day = "21",

doi = "10.1002/chem.202203967",

language = "English",

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Tröster, A, DiPrima, M, Jores, N, Kudlinzki, D, Sreeramulu, S, Gande, SL, Linhard, V, Ludig, D, Schug, A, Saxena, K, Reinecke, M, Heinzlmeir, S, Leisegang, MS, Wollenhaupt, J, Lennartz, F, Weiss, MS, Kuster, B, Tosato, G & Schwalbe, H 2023, 'Optimization of the Lead Compound NVP-BHG712 as a Colorectal Cancer Inhibitor', Chemistry - A European Journal, vol. 29, no. 23, e202203967. https://doi.org/10.1002/chem.202203967

TY - JOUR

T1 - Optimization of the Lead Compound NVP-BHG712 as a Colorectal Cancer Inhibitor

AU - Tröster, Alix

AU - DiPrima, Michael

AU - Jores, Nathalie

AU - Kudlinzki, Denis

AU - Sreeramulu, Sridhar

AU - Gande, Santosh L.

AU - Linhard, Verena

AU - Ludig, Damian

AU - Schug, Alexander

AU - Saxena, Krishna

AU - Reinecke, Maria

AU - Heinzlmeir, Stephanie

AU - Leisegang, Matthias S.

AU - Wollenhaupt, Jan

AU - Lennartz, Frank

AU - Weiss, Manfred S.

AU - Kuster, Bernhard

AU - Tosato, Giovanna

AU - Schwalbe, Harald

PY - 2023/4/21

Y1 - 2023/4/21

N2 - 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.

AB - 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.

KW - EPH receptors

KW - colorectal cancer

KW - drug discovery

KW - medicinal chemistry

KW - structural biology

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U2 - 10.1002/chem.202203967

DO - 10.1002/chem.202203967

M3 - Article

AN - SCOPUS:85150489002

SN - 0947-6539

VL - 29

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 23

M1 - e202203967

ER -

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

Abstract

Keywords

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