2 research outputs found
Azaindole-Based Inhibitors of Cdc7 Kinase: Impact of the Pre-DFG Residue, Val 195
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
Pyrimidine-Based Tricyclic Molecules as Potent and Orally Efficacious Inhibitors of Wee1 Kinase
Aided by molecular modeling, compounds
with a pyrimidine-based
tricyclic scaffold were designed and confirmed to inhibit Wee1 kinase.
Structure–activity studies identified key pharmacophores at
the aminoaryl and halo-benzene regions responsible for binding affinity
with sub-nM <i>K</i><sub>i</sub> values. The potent inhibitors
demonstrated sub-μM activities in both functional and mechanism-based
cellular assays and also possessed desirable pharmacokinetic profiles.
The lead molecule, <b>31</b>, showed oral efficacy in potentiating
the antiproliferative activity of irinotecan, a cytotoxic agent, in
a NCI-H1299 mouse xenograft model