title: Synthesis and biological evaluation of novel phosphatidylinositol 3-kinase inhibitors: Solubilized 4-substituted benzimidazole analogs of 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474).
abstract: A range of 4-substituted derivatives 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) were prepared in a search for more soluble analogs. 4-Aminoalkoxy substituents provided the most potent derivatives, with the 4-O(CH2)3NMe2 analog (compound 14) being identified as displaying the best overall activity in combination with good aqueous solubility (25 mg/mL for the hydrochloride salt). This compound was tested in a U87MG xenograft model, but displayed less potency than ZSTK474 as a result of an unfavorable pharmacokinetic profile.
authors: 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
authors: Gordon W
authors: GW
authors: Rewcastle
authors: Swarna A
authors: SA
authors: Gamage
authors: Jack U
authors: JU
authors: Flanagan
authors: Jackie D
authors: JD
authors: Kendall
authors: William A
authors: WA
authors: Denny
authors: Bruce C
authors: BC
authors: Baguley
authors: Christina M
authors: CM
authors: Buchanan
authors: Mindy
authors: M
authors: Chao
authors: Philip
authors: P
authors: Kestell
authors: Sharada
authors: S
authors: Kolekar
authors: Woo-Jeong
authors: WJ
authors: Lee
authors: Claire L
authors: CL
authors: Lill
authors: Alisha
authors: A
authors: Malik
authors: Ripudaman
authors: R
authors: Singh
authors: Stephen M F
authors: SM
authors: Jamieson
authors: Peter R
authors: PR
authors: Shepherd
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D045325:HCT116 Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018398:Homeodomain Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D014227:Triazines; C510150:ZSTK474; C064658:RAG-1 protein