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Figure 1.
Fig. 1. (A) Chemical structures of compounds 1 to 4. (B) X-ray
crystallographic structure of CDK2 in complex with compound 3
(15). Atoms are color-coded as follows: protein carbon atoms,
green; nitrogen, blue; oxygen, red; sulfur, yellow; and bromine,
purple. The carbon atoms of compound 3 are shown in orange. The
indolinone (or oxindole) moiety of compound 3 was bound at the
back of the ATP site in a manner similar to that found for
members of the related series 2 in complex with fibroblast
growth factor (FGF) kinase (31). The oxindole amide group of 3
interacted with the strand of protein that connects the two
domains of CDK2, donating a hydrogen bond to the backbone
carbonyl of Glu81 and accepting a hydrogen bond from the
backbone NH of Leu83. The sulfonamidophenylhydrazone group
projected toward the opening of the cleft, with the sulfonamide
interacting with Asp86. The backbone NH of Asp86 donated a
hydrogen bond to one of the sulfonamide oxygen atoms, and the
side-chain carboxyl group accepted a hydrogen bond from the
sulfonamide amine function. (C) X-ray crystallographic structure
of compound 4 bound to CDK2-cyclin A. The carbon atoms of
compound 4 are shown in pink. The thiazole nitrogen atom at
position 5 of compound 4 accepted a hydrogen bond from Lys33,
and the thiazole sulfur atom at position 4 provided hydrophobic
interactions with Val18. The pyridyl substituent on the
sulfonamide group projected into solvent.
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