title: Inhibitors of the TAM subfamily of tyrosine kinases: synthesis and biological evaluation.
abstract: The TAM subfamily of Receptor Tyrosine Kinases (RTKs) contains three human proteins of therapeutical interest, Axl, Mer, and Tyro3. Our goal was to design a type II inhibitor specific for this family, i.e. able to interact with the allosteric pocket and with the hinge region of the kinase. We report the synthesis of several series of purine analogues of BMS-777607. The structural diversity of the designed inhibitors was expected to modify the interactions formed in the binding site and consequently to modulate their selectivity profiles. The most potent inhibitor 6g exhibits Kds of 39, 42, 65 and 200 nM against Axl, Mer, Met and Tyro3 respectively. Analysis of the affinity of 6g for active and inactive forms of Abl1, an RTK protein that does not belong to the TAM subfamily, together with the binding modes of 6g predicted by docking studies, indicates that 6g displays some selectivity for the TAM family and may act as a type II inhibitor.
authors: Institut Curie, CNRS, UMR 176, Bât. 110-112, Centre Universitaire, 91405 Orsay, France.
authors: Rosa M
authors: RM
authors: Suárez
authors: Franciane
authors: F
authors: Chevot
authors: Andrea
authors: A
authors: Cavagnino
authors: Nicolas
authors: N
authors: Saettel
authors: François
authors: F
authors: Radvanyi
authors: Sandrine
authors: S
authors: Piguel
authors: Isabelle
authors: I
authors: Bernard-Pierrot
authors: Véronique
authors: V
authors: Stoven
authors: Michel
authors: M
authors: Legraverend
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases