Pyrimidine-based tricyclic molecules as potent and orally efficacious inhibitors of wee1 kinase.
2015
Aided by
molecular modeling, compounds with a pyrimidine-based
tricyclicscaffold were designed and confirmed to inhibit
Wee1kinase. Structure–activity studies identified key
pharmacophoresat the aminoaryl and halo-benzene regions responsible for binding affinity with sub-nM Ki 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, 31, showed oral efficacy in potentiating the antiproliferative activity of
irinotecan, a cytotoxic agent, in a NCI-H1299 mouse xenograft model.
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