title: Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941.
abstract: The phosphatidylinositide 3-kinase pathway is frequently deregulated in human cancers and inhibitors offer considerable therapeutic potential. We previously described the promising tricyclic pyridofuropyrimidine lead and chemical tool compound PI-103. We now report the properties of the pharmaceutically optimized bicyclic thienopyrimidine derivatives PI-540 and PI-620 and the resulting clinical development candidate GDC-0941. All four compounds inhibited phosphatidylinositide 3-kinase p110alpha with IC(50) < or = 10 nmol/L. Despite some differences in isoform selectivity, these agents exhibited similar in vitro antiproliferative properties to PI-103 in a panel of human cancer cell lines, with submicromolar potency in PTEN-negative U87MG human glioblastoma cells and comparable phosphatidylinositide 3-kinase pathway modulation. PI-540 and PI-620 exhibited improvements in solubility and metabolism with high tissue distribution in mice. Both compounds gave improved antitumor efficacy over PI-103, following i.p. dosing in U87MG glioblastoma tumor xenografts in athymic mice, with treated/control values of 34% (66% inhibition) and 27% (73% inhibition) for PI-540 (50 mg/kg b.i.d.) and PI-620 (25 mg/kg b.i.d.), respectively. GDC-0941 showed comparable in vitro antitumor activity to PI-103, PI-540, and PI-620 and exhibited 78% oral bioavailability in mice, with tumor exposure above 50% antiproliferative concentrations for >8 hours following 150 mg/kg p.o. and sustained phosphatidylinositide 3-kinase pathway inhibition. These properties led to excellent dose-dependent oral antitumor activity, with daily p.o. dosing at 150 mg/kg achieving 98% and 80% growth inhibition of U87MG glioblastoma and IGROV-1 ovarian cancer xenografts, respectively. Together, these data support the development of GDC-0941 as a potent, orally bioavailable inhibitor of phosphatidylinositide 3-kinase. GDC-0941 has recently entered phase I clinical trials.
authors: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK. florence.raynaud@icr.ac.uk
authors: Florence I
authors: FI
authors: Raynaud
authors: Suzanne A
authors: SA
authors: Eccles
authors: Sonal
authors: S
authors: Patel
authors: Sonia
authors: S
authors: Alix
authors: Gary
authors: G
authors: Box
authors: Irina
authors: I
authors: Chuckowree
authors: Adrian
authors: A
authors: Folkes
authors: Sharon
authors: S
authors: Gowan
authors: Alexis
authors: A
authors: De Haven Brandon
authors: Francesca
authors: F
authors: Di Stefano
authors: Angela
authors: A
authors: Hayes
authors: Alan T
authors: AT
authors: Henley
authors: Letitia
authors: L
authors: Lensun
authors: Giles
authors: G
authors: Pergl-Wilson
authors: Anthony
authors: A
authors: Robson
authors: Nahid
authors: N
authors: Saghir
authors: Alexander
authors: A
authors: Zhyvoloup
authors: Edward
authors: E
authors: McDonald
authors: Peter
authors: P
authors: Sheldrake
authors: Stephen
authors: S
authors: Shuttleworth
authors: Melanie
authors: M
authors: Valenti
authors: Nan Chi
authors: NC
authors: Wan
authors: Paul A
authors: PA
authors: Clarke
authors: Paul
authors: P
authors: Workman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005663:Furans / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D013876:Thiophenes / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; D007191:Indazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D013876:Thiophenes; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C544306:PI 540; C544307:PI 620; C522973:PI103; C546842:MTOR protein, human; C546843:mTOR protein, mouse