title: Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases.
abstract: Extensive evidence implicates activation of the lipid phosphatidylinositide 3-kinase (PI3K) pathway in the genesis and progression of various human cancers. PI3K inhibitors thus have considerable potential as molecular cancer therapeutics. Here, we detail the pharmacologic properties of a prototype of a new series of inhibitors of class I PI3K. PI103 is a potent inhibitor with low IC50 values against recombinant PI3K isoforms p110alpha (2 nmol/L), p110beta (3 nmol/L), p110delta (3 nmol/L), and p110gamma (15 nmol/L). PI103 also inhibited TORC1 by 83.9% at 0.5 micromol/L and exhibited an IC50 of 14 nmol/L against DNA-PK. A high degree of selectivity for the PI3K family was shown by the lack of activity of PI103 in a panel of 70 protein kinases. PI103 potently inhibited proliferation and invasion of a wide variety of human cancer cells in vitro and showed biomarker modulation consistent with inhibition of PI3K signaling. PI103 was extensively metabolized, but distributed rapidly to tissues and tumors. This resulted in tumor growth delay in eight different human cancer xenograft models with various PI3K pathway abnormalities. Decreased phosphorylation of AKT was observed in U87MG gliomas, consistent with drug levels achieved. We also showed inhibition of invasion in orthotopic breast and ovarian cancer xenograft models and obtained evidence that PI103 has antiangiogenic potential. Despite its rapid in vivo metabolism, PI103 is a valuable tool compound for exploring the biological function of class I PI3K and importantly represents a lead for further optimization of this novel class of targeted molecular cancer therapeutic.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow and McElwain Laboratories, Sutton, Surrey, United Kingdom. Florence.Raynaud@icr.ac.uk
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Suzanne
authors.initials: S
authors.lastname: Eccles
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clarke
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.forename: Bernard
authors.initials: B
authors.lastname: Nutley
authors.forename: Sonia
authors.initials: S
authors.lastname: Alix
authors.forename: Alan
authors.initials: A
authors.lastname: Henley
authors.forename: Francesca
authors.initials: F
authors.lastname: Di-Stefano
authors.forename: Zahida
authors.initials: Z
authors.lastname: Ahmad
authors.forename: Sandrine
authors.initials: S
authors.lastname: Guillard
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Bjerke
authors.forename: Lloyd
authors.initials: L
authors.lastname: Kelland
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.forename: Lisa
authors.initials: L
authors.lastname: Patterson
authors.forename: Sharon
authors.initials: S
authors.lastname: Gowan
authors.forename: Alexis
authors.initials: A
authors.lastname: de Haven Brandon
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kaizawa
authors.forename: Tomonubu
authors.initials: T
authors.lastname: Koizumi
authors.forename: Takahide
authors.initials: T
authors.lastname: Ohishi
authors.forename: Sonal
authors.initials: S
authors.lastname: Patel
authors.forename: Nahid
authors.initials: N
authors.lastname: Saghir
authors.forename: Peter
authors.initials: P
authors.lastname: Parker
authors.forename: Mike
authors.initials: M
authors.lastname: Waterfield
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D009369:Neoplasms / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005663:Furans; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011743:Pyrimidines; C522973:PI103