N

NH CO

Cys-919

FIGURE 9.12 Binding of AAL-993 to VEGFR-2.

inhibitors and later refined to give VEGFR-2 (KDR)-selective compounds. Vandeta-nib occupies the ATP adenine binding site, where it forms a single hydrogen bond involving its N-1 nitrogen and the Cys-912 residue of the protein. Several structure-activity relationships have been deduced for this family, including an increased activity for the 2-fluoro and 5-hydroxy derivatives, the latter effect being attributed to the formation of an additional hydrogen bond.27

Other promising quinazoline derivatives that act on VEGFR are AZD-2171 (ZD-2171), which demonstrated >800- to 5000-fold in vitro selectivity for VEGFR-2 inhibition, compared with a range of tyrosine and serine-threonine kinases. It is undergoing a number of clinical trials (Phase I, Phase II/III) to evaluate its role in a range of solid tumors.28 GW-786034 is another orally active quinazoline that is also in clinical trials.29

Vandetanib (ZD6474)

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