Abstract 2083: Toxicity, bioavailability, pharmacokinetics, tissue distribution and metabolism of a novel small molecule inhibitor of IL-6-induced STAT3 activation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (14_Supplement), p.2083-2083
• Main Authors: Kiesel, Brian F., Parise, Robert A., Guo, Jianxia, Huryn, Donna M., Johnston, Paul A., Colombo, Rafaelle, Sen, Malabika, Grandis, Jennifer, Eiseman, Julie L., Beumer, Jan H.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-2083

Introduction: The oncogenic transcription factor STAT3 is frequently hyper-activated in head and neck cancer and promotes gene transcription involved in cancer development, maintenance and progression. Several selective small molecule inhibitors of IL-6-induced STAT3 activation were identified in a screening campaign, and four analogs from a lead optimization series were analyzed. Compound UPCDC10205 was prioritized for in vivo testing to evaluate its toxicity, pharmacokinetics (PK) and metabolism in mice. Methods: The four inhibitors of IL-6-induced STAT3 activation were incubated with liver microsomes from Foxn1 +/nu mice up to 90 min. An LC-MS/MS assay was developed to quantify substrate depletion. Single IV dose toxicity was determined in male and female Foxn1 +/nu mice at the maximum soluble dose of 4 mg/kg of compound UPCDC10205 in 10% Solutol. In the multiple IV dose study in female mice UPCDC10205 was dosed QDx5 at 4, 2.7, and 1.3 mg/kg/day. During toxicity studies clinical health status was observed daily and body weight was recorded twice weekly for 14 days after treatment, followed by necropsy. To evaluate PK, single doses of UPCDC10205 IV 4 mg/kg, PO IV 4 mg/kg, or PO 30 mg/kg UPCDC10205 suspension in 1% CMC, were administered to groups of female mice. Mice were euthanized from 5 min to 24 h after dosing (n = 3). RBCs, plasma and tissues were collected and stored at -80 °C. UPCDC10205 concentrations were quantified by LC-MS/MS. Non-compartmental PK were evaluated. LC-MS/MS was used to screen for metabolites in plasma and urine. Results: Approximately 80% of compound UPCDC10205 remained after a 90 min microsomal incubation compared to