Design, synthesis, biological evaluation and cellular imaging of imidazo[4,5-b]pyridine derivatives as potent and selective TAM inhibitors

被引：10

作者：

Baladi, Tom ^{[1
,2
]}

Aziz, Jessy ^{[1
]}

Dufour, Florent ^{[3
]}

Abet, Valentina ^{[1
]}

Stoven, Veronique ^{[4
,5
]}

Radvanyi, Francois ^{[3
]}

Poyer, Florent ^{[1
]}

Wu, Ting-Di ^{[1
]}

Guerquin-Kern, Jean-Luc ^{[1
]}

Bernard-Pierrot, Isabelle ^{[3
]}

Garrido, Sergio Marco ^{[1
]}

Piguel, Sandrine ^{[1
,2
]}

机构：

[1] PSL Res Univ, Inst Curie, CNRS, INSERM,UMR9187,U1196, F-91405 Orsay, France

[2] Univ Paris Saclay, Univ Paris Sud, F-91405 Orsay, France

[3] PSL Res Univ, Inst Curie, CNRS, UMR 144, F-75248 Paris 05, France

[4] PSL Res Univ, Inst Curie, INSERM, U900, F-75248 Paris 05, France

[5] Mines ParisTech, CBIO Ctr Computat Biol, 35 Rue St Honore, F-77300 Fontainebleau, France

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2018年 / 26卷 / 20期

关键词：

Kinase inhibitors; AXL; TYRO3; MER; Imidazopyridines; NanoSIMS imaging; RECEPTOR TYROSINE KINASES; DISCOVERY; FAMILY; IMIDAZOPYRIDINE; OPTIMIZATION; MODELS; CANCER;

D O I：

10.1016/j.bmc.2018.09.031

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 TAM kinase family arises as a new effective and attractive therapeutic target for cancer therapy, autoimmune and viral diseases. A series of 2,6-disubstituted imidazo[4,5-b] pyridines were designed, synthesized and identified as highly potent TAM inhibitors. Despite remarkable structural similarities within the TAM family, compounds 28 and 25 demonstrated high activity and selectivity in vitro against AXL and MER, with IC50 value of 0.77 nM and 9 nM respectively and a 120- to 900-fold selectivity. We also observed an unexpected nuclear localization for compound 10Bb, thanks to nanoSIMS technology, which could be correlated to the absence of cytotoxicity on three different cancer cell lines being sensitive to TAM inhibition.

引用

收藏

页码：5510 / 5530

页数：21

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