Fig. 2.
Structural basis for ALK kinase inhibition selectivity by TAE684. (A) Model of ALK in complex with TAE684, developed based on the published crystal structure of InsR in an “active” conformation by using homology modeling (MOE). TAE684 is expected to bind to the ATP-binding site by using a bidentate hydrogen bonding pair to the kinase “hinge” region of ALK. The orthomethoxy group attached to the 2-aniline substitutent is anticipated to project into a small groove located between the side chains of residues L258 and M259. (B) Position L258 is one of the major determinants for ALK selectivity of TAE684. Substitution of leucine with a bulkier amino acid such as phenylalanine (F258) induces a conformational change that leads to a steric clash of the hinge region with TAE684.