title: Preclinical pharmacological evaluation of a novel multiple kinase inhibitor, ON123300, in brain tumor models.
abstract: ON123300 is a low molecular weight multikinase inhibitor identified through a series of screens that supported further analyses for brain tumor chemotherapy. Biochemical assays indicated that ON123300 was a strong inhibitor of Ark5 and CDK4, as well as growth factor receptor tyrosine kinases such as β-type platelet-derived growth factor receptor (PDGFRβ). ON123300 inhibited U87 glioma cell proliferation with an IC(50) 3.4 ± 0.1 μmol/L and reduced phosphorylation of Akt, yet it also unexpectedly induced Erk activation, both in a dose- and time-dependent manner that subsequently was attributed to relieving Akt-mediated C-Raf S259 inactivation and activating a p70S6K-initiated PI3K-negative feedback loop. Cotreatment with the EGFR inhibitor gefitinib produced synergistic cytotoxic effects. Pursuant to the in vitro studies, in vivo pharmacokinetic and pharmacodynamic studies of ON123300 were completed in mice bearing intracerebral U87 tumors following intravenous doses of 5 and 25 mg/kg alone, and also at the higher dose concurrently with gefitinib. ON123300 showed high brain and brain tumor accumulation based on brain partition coefficient values of at least 2.5. Consistent with the in vitro studies, single agent ON123300 caused a dose-dependent suppression of phosphorylation of Akt as well as activation of Erk in brain tumors, whereas addition of gefitinib to the ON123300 regimen significantly enhanced p-Akt inhibition and prevented Erk activation. In summary, ON123300 demonstrated favorable pharmacokinetic characteristics, and future development for brain tumor therapy would require use of combinations, such as gefitinib, that mitigate its Erk activation and enhance its activity.
authors.affiliation: Authors' Affiliations: Departments of Pharmacology and Systems Therapeutics and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Pharmaceutical Science, University of South Florida, Tampa, Florida.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Lv
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Zhou
authors.forename: Rana
authors.initials: R
authors.lastname: Elkholi
authors.forename: Jerry E
authors.initials: JE
authors.lastname: Chipuk
authors.forename: M V Ramana
authors.initials: MV
authors.lastname: Reddy
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
authors.forename: James M
authors.initials: JM
authors.lastname: Gallo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000594117:ON123300; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt