861774-96-1Relevant academic research and scientific papers
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.,Frederick, Raphael,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.
, p. 7105 - 7126 (2011/12/04)
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 ?- 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
