Synthesis and biological evaluation of novel analogues of the pan class i phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(Difluoromethyl)-1-[4,6-di(4- morpholinyl)-1,3,5-triazin-2-yl]-1 H -benzimidazole (ZSTK474)

G.W. Rewcastle, S.A. Gamage, J.U. Flanagan, R. Frederick, W.A. Denny, B.C. Baguley, P. Kestell, R. Singh, J.D. Kendall, E.S. Marshall, C.L. Lill, S.M.F. Jamieson, C.M. Buchanan, P.R. Shepherd, W.-J. Lee, S. Kolekar

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Abstract

A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2- yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1 mice, and at a dose of 50 mg/kg given by ip injection at a qd ø- 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
Original languageEnglish
Pages (from-to)7105-7126
Number of pages22
JournalJournal of Medicinal Chemistry
Volume54
Issue number20
DOIs
Publication statusPublished - 27 Oct 2011

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