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

被引：7

作者：

Unzue, Andrea ^{[1
]}

Jessen-Trefzer, Claudia ^{[1
]}

Spiliotopoulos, Dimitrios ^{[2
]}

Gaudio, Eugenio ^{[3
]}

Tarantelli, Chiara ^{[3
]}

Dong, Jing ^{[2
]}

Zhao, Hongtao ^{[2
]}

Pachmayr, Johanna ^{[4
]}

Zahler, Stefan ^{[4
]}

Bernasconi, Elena ^{[3
]}

Sartori, Giulio ^{[3
]}

Cascione, Luciano ^{[3
,5
]}

Bertoni, Francesco ^{[3
,6
]}

Sledz, Pawel ^{[2
]}

Caflisch, Amedeo ^{[2
]}

Nevado, Cristina ^{[1
]}

机构：

[1] Univ Zurich, Dept Chem, Winterthurerstr 190, CH-8057 Zurich, Switzerland

[2] Univ Zurich, Dept Biochem, Winterthurerstr 190, CH-8057 Zurich, Switzerland

[3] USI, Fac Biomed Sci, Inst Oncol Res, Bellinzona, Switzerland

[4] Univ Munich, Dept Pharm, Butenandstr 5-13, D-81377 Munich, Germany

[5] SIB Swiss Inst Bioinformat, Lausanne, Switzerland

[6] Oncol Inst Southern Switzerland IOSI, Bellinzona, Switzerland

来源：

RSC MEDICINAL CHEMISTRY | 2020年 / 11卷 / 06期

基金：

瑞士国家科学基金会;

关键词：

CHRONIC MYELOID-LEUKEMIA; P38 MAP KINASE; TYROSINE KINASE; CONNECTIVITY MAP; DISCOVERY; BINDING; OPTIMIZATION; DASATINIB; IMATINIB; DOCKING;

D O I：

10.1039/d0md00049c

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 andin vivoin a relevant lymphoma model, showed high efficacy in the control of tumor size.

引用

页码：665 / 675

页数：11

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