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]-1H-benzimidazole (ZSTK474)

Gordon W Rewcastle; Swarna A Gamage; Jack U Flanagan; Raphael Frederick; William A Denny; Bruce C Baguley; Philip Kestell; Ripudaman Singh; Jackie D Kendall; Elaine S Marshall; Claire L Lill; Woo-Jeong Lee; Sharada Kolekar; Christina M Buchanan; Stephen M F Jamieson; Peter R Shepherd

doi:10.1021/jm200688y

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]-1H-benzimidazole (ZSTK474)

J Med Chem. 2011 Oct 27;54(20):7105-26. doi: 10.1021/jm200688y. Epub 2011 Sep 27.

Authors

Gordon W Rewcastle¹, Swarna A Gamage, Jack U Flanagan, Raphael Frederick, William A Denny, Bruce C Baguley, Philip Kestell, Ripudaman Singh, Jackie D Kendall, Elaine S Marshall, Claire L Lill, Woo-Jeong Lee, Sharada Kolekar, Christina M Buchanan, Stephen M F Jamieson, Peter R Shepherd

Affiliation

¹ Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. g.rewcastle@auckland.ac.nz

PMID: 21882832
DOI: 10.1021/jm200688y

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 × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Benzimidazoles / chemical synthesis*
Benzimidazoles / pharmacokinetics
Benzimidazoles / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Female
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / genetics
Isoenzymes / metabolism
Male
Mice
Mice, Knockout
Models, Molecular
Mutation
Neoplasm Transplantation
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Phosphorylation
Signal Transduction / drug effects
Solubility
Structure-Activity Relationship
Transplantation, Heterologous
Triazines / chemical synthesis*
Triazines / pharmacokinetics
Triazines / pharmacology

Substances

Antineoplastic Agents
Benzimidazoles
Isoenzymes
Phosphoinositide-3 Kinase Inhibitors
Triazines
ZSTK474