Abstract 2083: Toxicity, bioavailability, pharmacokinetics, tissue distribution and metabolism of a novel small molecule inhibitor of IL-6-induced STAT3 activation
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. 
Published: July 2016

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 &lt;50% for the other analogs. Mice exhibited no signs of toxicity after single or multiple doses of 4 mg/kg IV. Exposure in liver, lungs, kidney, skeletal muscle and brain were 1.6-3.2-fold that of plasma. Plasma AUC after IV 4 mg/kg (1022 ng/mL*h) compared to PO 4 mg/kg dosing (53 ng/mL*h) yielding a bioavailability of ∼5%. Compound UPCDC10205 was not detected beyond 6 h in any tissue. The plasma half-life was 0.6 h, clearance 3.9 L/h/kg and distribution volume 3.4 L/kg. The major metabolite identified in both plasma and urine was UPCDC10205 N-glucuronide

Conclusion: In vitro, UPCDC10205 was metabolically stable. No gross toxicity was observed in mice administered the maximum soluble dose. UPCDC10205 was widely distributed into tissues and cleared rapidly. Bioavailability was ∼5%. In vivo metabolism of UPCDC10205 was by direct glucuronidation, explaining why microsomal stability (reflective of phase I metabolism) did not translate to in vivo metabolic stability.

Support: P30CA047904; P50CA097190

Citation Format: Brian F. Kiesel, Robert A. Parise, Jianxia Guo, Donna M. Huryn, Paul A. Johnston, Rafaelle Colombo, Malabika Sen, Jennifer Grandis, Julie L. Eiseman, Jan H. Beumer. Toxicity, bioavailability, pharmacokinetics, tissue distribution and metabolism of a novel small molecule inhibitor of IL-6-induced STAT3 activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2083.