title: In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models.
abstract: OBJECTIVE
  To evaluate the therapeutic and biological effects of CHIR-258, an orally bioavailable, potent inhibitor of class III-V receptor tyrosine kinases, in colon cancer models.
  
  
  METHODS
  The pharmacologic activity of CHIR-258 was characterized by monitoring target modulation as well as by evaluating the antitumor and antiangiogenic effects in human colon xenograft models.
  
  
  RESULTS
  CHIR-258 inhibits vascular endothelial growth factor receptor 1/2, fibroblast growth factor receptor 1/3, and platelet-derived growth factor receptor beta (PDGFRbeta) and shows both antitumor and antiangiogenic activities in vivo. Treatment of KM12L4a human colon cancer cells with CHIR-258 resulted in a dose-dependent inhibition of vascular endothelial growth factor receptor 1 and PDGFRbeta phosphorylation and reduction of phosphorylated extracellular signal-regulated kinase (ERK) levels, indicating modulation of target receptors and downstream signaling. In vivo administration of CHIR-258 resulted in significant tumor growth inhibition and tumor regressions, including large, established tumors (500-1,000 mm(3)). Immunohistochemical analysis showed a reduction of phosphorylated PDGFRbeta and phosphorylated ERK in tumor cells after oral dosing with CHIR-258 compared with control tumors. These changes were accompanied by decreased tumor cell proliferation rate and reduced intratumoral microvessel density. CHIR-258 inhibited the phosphorylation of PDGFRbeta and ERK phosphorylation in tumors within 2 hours following dosing and the inhibitory activity was sustained for >24 hours. Significant antitumor activity was observed with intermittent dosing schedules, indicating a sustained biological activity.
  
  
  CONCLUSIONS
  These studies provide evidence that biological activity of CHIR-258 in tumors correlates with efficacy and aids in the identification of potential biomarkers of this multitargeted receptor tyrosine kinase inhibitor. CHIR-258 exhibits properties that make it a promising candidate for clinical development in a variety of solid and hematologic malignancies.
authors.affiliation: Department of Pharmacology, Chiron Corp., Emeryville, California, USA.
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Daniel
authors.initials: D
authors.lastname: Lopes de Menezes
authors.forename: Jayesh
authors.initials: J
authors.lastname: Vora
authors.forename: Alex
authors.initials: A
authors.lastname: Harris
authors.forename: Helen
authors.initials: H
authors.lastname: Ye
authors.forename: Lara
authors.initials: L
authors.lastname: Nordahl
authors.forename: Evelyn
authors.initials: E
authors.lastname: Garrett
authors.forename: Emil
authors.initials: E
authors.lastname: Samara
authors.forename: Sharon Lea
authors.initials: SL
authors.lastname: Aukerman
authors.forename: Arnold B
authors.initials: AB
authors.lastname: Gelb
authors.forename: Carla
authors.initials: C
authors.lastname: Heise
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D005260:Female; D006133:Growth Substances / Q000096:biosynthesis*; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D006133:Growth Substances; D020574:Proto-Oncogene Proteins c-sis; D015363:Quinolones; D040281:Vascular Endothelial Growth Factor Receptor-1