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

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.

SUBMITTER: Unzue A

PROVIDER: S-EPMC7557569 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Unzue Andrea A Jessen-Trefzer Claudia C Spiliotopoulos Dimitrios D Gaudio Eugenio E Tarantelli Chiara C Dong Jing J Zhao Hongtao H Pachmayr Johanna J Zahler Stefan S Bernasconi Elena E Sartori Giulio G Cascione Luciano L Bertoni Francesco F Śledź Paweł P Caflisch Amedeo A Nevado Cristina C

RSC medicinal chemistry 20200519 6

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 therap ...[more]

PMID: 33479666

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