Homology model of Kit kinase with SU6597 docked into the ATP binding site. A homology model was constructed for SU6597 bound to the Kit kinase domain based on the co-crystal of FGFr1 with SU6668. SU6597 differs from the SU5416 parent drug by addition of a propionic acid moiety to the 4 position of the pyrrole and a Cl to the 5 position of the oxindole core. Addition of the propionic acid moiety allowed the formation of the illustrated additional contacts with the peptide amide of Asp677 and the side chain of Asn680, partially accounting for SU6597's markedly increased potency against Kit in biochemical assays. Cellular potency in a model system and SCLC cell lines was not enhanced however, illustrating the complexity of optimizing tyrosine kinase inhibitors for therapeutic use. For details, see the article by Krystal et al. on p. 3660 in this issue.