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: Florence I Raynaud, Suzanne A Eccles, Sonal Patel, Sonia Alix, Gary Box, Irina Chuckowree, Adrian Folkes, Sharon Gowan, Alexis De Haven Brandon, Francesca Di Stefano, Angela Hayes, Alan T Henley, Letitia Lensun, Giles Pergl-Wilson, Anthony Robson, Nahid Saghir, Alexander Zhyvoloup, Edward McDonald, Peter Sheldrake, Stephen Shuttleworth, Melanie Valenti, Nan Chi Wan, Paul A Clarke, Paul Workman
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 7 Pg. 1725-38 (Jul 2009) ISSN: 1538-8514 [Electronic] United States
• PMID: 19584227 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
• Enzyme Inhibitors
• Furans
• Indazoles
• PI 540
• PI 620
• PI103
• Phosphoinositide-3 Kinase Inhibitors
• Pyridines
• Pyrimidines
• Sulfonamides
• Thiophenes
• Protein Kinases
• MTOR protein, human
• mTOR protein, mouse
• TOR Serine-Threonine Kinases

Topics

• Administration, Oral
• Animals
• Cell Proliferation (drug effects)
• Cells, Cultured
• Endothelium, Vascular (drug effects, metabolism)
• Enzyme Inhibitors (pharmacology)
• Female
• Furans (pharmacology)
• Glioblastoma (drug therapy, enzymology, pathology)
• Humans
• Indazoles (pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Structure
• Ovarian Neoplasms (drug therapy, enzymology, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinases (metabolism)
• Pyridines (pharmacology)
• Pyrimidines (administration & dosage, pharmacokinetics, pharmacology)
• Sulfonamides (pharmacology)
• TOR Serine-Threonine Kinases
• Thiophenes (administration & dosage, pharmacokinetics, pharmacology)
• Umbilical Veins (cytology)
• Xenograft Model Antitumor Assays