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)

Rewcastle, Gordon W. [/] Gamage, Swarna A. [/] Flanagan, Jack U. [/] Frédérick, Raphaël [UCL] Denny, William A. [/] Baguley, Bruce C. [/] Kestell, Philip [/] Singh, Ripudaman [/] Kendall, Jackie D. [/] Marshall, Elaine S. [/] Lill, Claire L. [/] Lee, Woo-Jeong [/] Kolekar, Sharada [/] Buchanan, Christina M. [/] Jamieson, Stephen M.F. [/] Shepherd, Peter R. [/] et al.[show all]

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. © 2011 American Chemical Society.