Preclinical Toxicology Studies With Y15, A Novel Focal Adhesion Kinase (Fak) Inhibitor.
JOURNAL OF CLINICAL ONCOLOGY(2013)
Abstract
e13561 Background: Focal Adhesion Kinase (FAK) is overexpressed in many types of tumors and plays a major role in survival signaling. Recently, we developed a FAK scaffolding inhibitor, Y15 that targeted the main FAK autophosphorylation site (Y397) and had high efficacy in blocking tumor growth in many xenograft mice models. We performed a small animal toxicology study of Y15 and detected the maximal tolerated dose of this drug in mice. Methods: The toxicology study was performed in CD-1 albino [Hsd:ICR(CD-1)] mice with Y15 inhibitor delivered either by intraperitoneal injection (IP) or by oral delivery. Clinical chemistry data were collected by Hemagen Analyst II automatic Chemistry analyzer. In addition, hematology, body weight, mortality, and histopathology on different organs were analyzed in all mice. Results: We delivered Y15 by IP injection at 15 (low), 30 (medium) and 45 mg/kg (high) doses daily for 5 days/week during a 28 day study, or orally by gavage at 100 and 200 mg/kg daily during a 7 day study. The maximal tolerated dose by IP during 28 day study was 30 mg/kg. The maximal tolerated dose during single oral dose administration was 200 mg/kg and 100 mg/kg during 7 day study. Y15 did not cause any mortality or statistically significant differences in the body weight at 30mg/kg IP delivery during a 28-day study and at 100 mg/kg by oral delivery during a 7 day study. There were no significant clinical chemistry changes in alkaline phosphatase, gamma glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, amylase, blood urea nitrogen, glucose, phosphorus, calcium, albumin, cholesterol, creatine kinase, total bilirubin, total protein and globulin. Finally, no significant histopathological changes were observed by necropsy in different organs at 30 mg/kg by IP and at 100 mg/kg dose by oral delivery. Conclusions: The Y15 FAK autophosphorylation inhibitor is well tolerated in mice and caused no significant toxicity by IP and oral delivery, suggesting it is a promising candidate for further large animal toxicology study prior to human trials.
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Key words
novel focal adhesion kinase,y15,inhibitor,preclinical toxicology studies
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