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

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

  • RSC Med Chem. 2020 May 19;11(6):665-675. doi: 10.1039/d0md00049c.
Andrea Unzue 1,  Claudia Jessen-Trefzer 1,  Dimitrios Spiliotopoulos 2,  Eugenio Gaudio 3,  Chiara Tarantelli 3,  Jing Dong 2,  Hongtao Zhao 2,  Johanna Pachmayr 4,  Stefan Zahler 4,  Elena Bernasconi 3,  Giulio Sartori 3,  Luciano Cascione 3 5,  Francesco Bertoni 3 6,  Paweł Śledź 2,  Amedeo Caflisch 2,  Cristina Nevado 1
Affiliations

Affiliations

  • 1 Department of Chemistry , University of Zurich , Winterthurerstrasse 190 , CH-8057 , Zürich , Switzerland . Email: cristina.nevado@chem.uzh.ch ; ; Tel: (+41) 446353945.
  • 2 Department of Biochemistry , University of Zurich , Winterthurerstrasse 190 , CH-8057 , Zürich , Switzerland.
  • 3 Institute of Oncology Research , Faculty of Biomedical Sciences , USI , Bellinzona , Switzerland.
  • 4 Department of Pharmacy , University of Munich , Butenandstrasse 5-13 , 81377 Munich , Germany.
  • 5 SIB Swiss Institute of Bioinformatics , Lausanne , Switzerland.
  • 6 Oncology Institute of Southern Switzerland (IOSI) , Bellinzona , Switzerland.
PMID: 33479666 DOI: 10.1039/d0md00049c
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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