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

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

  • Bioorg Med Chem. 2018 Nov 1;26(20):5510-5530. doi: 10.1016/j.bmc.2018.09.031.
Tom Baladi 1,  Jessy Aziz 2,  Florent Dufour 3,  Valentina Abet 2,  Véronique Stoven 4,  François Radvanyi 3,  Florent Poyer 2,  Ting-Di Wu 2,  Jean-Luc Guerquin-Kern 2,  Isabelle Bernard-Pierrot 3,  Sergio Marco Garrido 2,  Sandrine Piguel 5
Affiliations

Affiliations

  • 1 Institut Curie, PSL Research University, CNRS, INSERM, UMR9187-U1196, F-91405 Orsay, France; Université Paris Sud, Université Paris-Saclay, F-91405 Orsay, France.
  • 2 Institut Curie, PSL Research University, CNRS, INSERM, UMR9187-U1196, F-91405 Orsay, France.
  • 3 Institut Curie, PSL Research University, CNRS, UMR 144, F-75248 Paris 05, France.
  • 4 Institut Curie, PSL Research University, INSERM U900, F-75248 Paris 05, France; Mines ParisTech, CBIO - Centre for Computational Biology, 35 rue Saint-Honoré, F-77300 Fontainebleau, France.
  • 5 Institut Curie, PSL Research University, CNRS, INSERM, UMR9187-U1196, F-91405 Orsay, France; Université Paris Sud, Université Paris-Saclay, F-91405 Orsay, France. Electronic address: sandrine.piguel@curie.fr.
PMID: 30309671 DOI: 10.1016/j.bmc.2018.09.031
Abstract

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.

Keywords

AXL; Imidazopyridines; Kinase inhibitors; MER; NanoSIMS imaging; TYRO3.

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