1 research outputs found
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