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Understanding the mechanism of action of pyrrolo[3,2-b]quinoxaline-derivatives as kinase inhibitors


Unzue, Andrea; Jessen-Trefzer, Claudia; Spiliotopoulos, Dimitrios; Gaudio, Eugenio; Tarantelli, Chiara; Dong, Jing; Zhao, Hongtao; Pachmayr, Johanna; Zahler, Stefan; Bernasconi, Elena; Sartori, Giulio; Cascione, Luciano; Bertoni, Francesco; Śledź, Paweł; Caflisch, Amedeo; Nevado, Cristina (2020). Understanding the mechanism of action of pyrrolo[3,2-b]quinoxaline-derivatives as kinase inhibitors. RSC Medicinal Chemistry, 11(6):665-675.

Abstract

The X-ray structure of the catalytic domain of the EphA3 tyrosine kinase in complex with a previously reported type II inhibitor was used to design two novel quinoxaline derivatives, inspired by kinase inhibitors that have reached clinical development. These two new compounds were characterized by an array of cell-based assays and gene expression profiling experiments. A global chemical proteomics approach was used to generate the drug-protein interaction profile, which suggested suitable therapeutic indications. Both inhibitors, studied in the context of angiogenesis and in vivo in a relevant lymphoma model, showed high efficacy in the control of tumor size.

Abstract

The X-ray structure of the catalytic domain of the EphA3 tyrosine kinase in complex with a previously reported type II inhibitor was used to design two novel quinoxaline derivatives, inspired by kinase inhibitors that have reached clinical development. These two new compounds were characterized by an array of cell-based assays and gene expression profiling experiments. A global chemical proteomics approach was used to generate the drug-protein interaction profile, which suggested suitable therapeutic indications. Both inhibitors, studied in the context of angiogenesis and in vivo in a relevant lymphoma model, showed high efficacy in the control of tumor size.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry

07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:1 January 2020
Deposited On:29 Jul 2020 09:40
Last Modified:03 May 2021 15:23
Publisher:Royal Society of Chemistry
ISSN:2632-8682
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1039/d0md00049c
PubMed ID:33479666

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