title: In vivo toxicity, metabolism and pharmacokinetic properties of FAK inhibitor 14 or Y15 (1, 2, 4, 5-benzenetetramine tetrahydrochloride).
abstract: Y15 or inhibitor 14 (1,2,4,5-benzenetetramine tetrahydrochloride) is a potent and specific inhibitor of focal adhesion kinase that inhibits its autophosphorylation activity, decreases the viability of cancer cells, and blocks tumor growth. In this preclinical study, we analyzed the pharmacokinetics of Y15 in mice plasma, its metabolic stability in mouse and human liver microsomes and toxicity in mice. The pharmacokinetics study in mice demonstrated that, following intraperitoneal administration at 30 mg/kg dose, Y15 was very rapidly absorbed in mice, reaching maximum plasma concentration in 4.8 min. Y15 rapidly metabolized in mouse and human liver microsomes with half-life t1/2 of 6.9 and 11.6 min, respectively. The maximal tolerated dose of single-dose administration of Y15 by oral administration was 200 mg/kg, and the multiple maximum tolerated dose of Y15 was 100 mg/kg by PO during 7 day study. Y15 did not cause any mortality or statistically significant differences in the body weight at 30 mg/kg by IP during 28-day study, and at 100 mg/kg by PO during the 7-day study. There were no clinical chemical, hematological, or histopathological changes in different mice organs at 30 mg/kg by IP during 28 days and at 100 mg/kg dose by PO during 7 days. Thus, this is the first preclinical toxicity, pharmacokinetics, and metabolic stability study of Y15 inhibitor. Further development of Y15 will provide a basis for new therapeutic and future clinical studies.
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14127, USA, vita.golubovskaya@roswellpark.org.
authors.forename: Vita
authors.initials: V
authors.lastname: Golubovskaya
authors.forename: Leslie
authors.initials: L
authors.lastname: Curtin
authors.forename: Adrienne
authors.initials: A
authors.lastname: Groman
authors.forename: Sandra
authors.initials: S
authors.lastname: Sexton
authors.forename: William G
authors.initials: WG
authors.lastname: Cance
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D001711:Biotransformation; D004355:Drug Stability; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D018570:Risk Assessment; D018675:Toxicity Tests
chemical_list: C539551:1,2,4,5-benzenetetraamine; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse