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.

Tumor Necrosis Factor-α (TNFα)-induced Ceramide Generation via Ceramide Synthases Regulates Loss of Focal Adhesion Kinase (FAK) and Programmed Cell Death

“…To tackle this question, the effects of the FAK inhibitor Y15 or inhibitor 14 on cell death were tested. The inhibitor Y15 is known to specifically inhibit the autophosphorylation of FAK (at Tyr-397) and decrease cancer cell viability and block tumor growth (55)(56)(57). As expected, Y15-treated cells showed a decrease in phosphorylated FAK (Tyr(P)-397) that occurred as early as 15 min post-treatment (Fig.…”

Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha

“…Fasudil, a small molecule ROCK inhibitor that has been approved for clinical use in Japan and shown to ameliorate experimental lung fibrosis, may be further explored for treatment of liver fibrosis. On the other hand, FAK inhibition has also been shown to prevent experimental lung fibrosis, and toxicity studies in vivo showed that FAK inhibitor 14 does not have significant systemic effects . Given our results showing that FAK is activated by levels of matrix rigidity measured in fibrotic livers and detected in hepatocytes near fibrotic tracts in vivo , it will be of interest in future studies to determine whether FAK inhibition may have a therapeutic role in chronic fibrotic liver disease.…”

In Vitro Activities of Hexaazatrinaphthylenes against Leishmania spp

“…during a 7-day study, has been published recently. There were no chemical, hematological, or histopathological clinical changes in different organs of mice at those two dosages (30).…”