Azaindole-Based Inhibitors
of Cdc7 Kinase: Impact
of the Pre-DFG Residue, Val 195
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Abstract
To investigate the role played by the unique pre-DFG
residue Val
195 of Cdc7 kinase on the potency of azaindole-chloropyridines (<b>1</b>), a series of novel analogues with various chloro replacements
were synthesized and evaluated for their inhibitory activity against
Cdc7. X-ray cocrystallization using a surrogate protein, GSK3β,
and modeling studies confirmed the azaindole motif as the hinge binder.
Weaker hydrophobic interactions with Met 134 and Val 195 by certain
chloro replacements (e.g., H, methyl) led to reduced Cdc7 inhibition.
Meanwhile, data from other replacements (e.g., F, O) indicated that
loss of such hydrophobic interaction could be compensated by enhanced
hydrogen bonding to Lys 90. Our findings not only provide an in-depth
understanding of the pre-DFG residue as another viable position impacting
kinase inhibition, they also expand the existing knowledge of ligand-Cdc7
binding