The Toxicology, Pharmacokinetics and Metabolism of a Novel IL-6 Induced STAT3 Inhibitor

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and annually an approximate 46,000 Americans are diagnosed and 8,600 Americans die from the disease. The oncogenic transcription factor STAT3 is frequently hyper-activated in HNSCC 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 to promote one to test in vivo.\ud To choose a lead compound for in vivo experimentation, the four compounds were incubated with mouse liver microsomes to select a lead based on enhanced metabolic stability. From this experiment compound UPCDC-10205 was prioritized for in vivo testing to evaluate its toxicity, pharmacokinetics (PK) and metabolism. Both single and multiple IV dose toxicity studies determined that the maximum soluble dose at 4 mg/kg of compound UPCDC-10205 in 10% Solutol™ was not toxic to mice. To evaluate PK, single doses of UPCDC-10205 IV 4 mg/kg, PO 4 mg/kg, or PO 30 mg/kg UPCDC-10205 suspension in 1% carboxymethyl cellulose were administered to groups of female mice that were euthanized from 5 min to 24 h after dosing. Plasma, urine and various tissues were analyzed using LC-MS to quantitate UPCDC-10205. PK parameters were determined non-compartmentally. Potential metabolites were monitored in plasma and urine using LC-MS.\ud PK analysis showed rapid plasma clearance and extensive distribution of UPCDC-10205. Comparisons of plasma exposure between 4 mg/kg PO and IV showed a bioavailability of ~5%. Little UPCDC-10205 was observed in urine, leading to the hypothesis that metabolism was the major contributor to clearance. Metabolic investigations revealed direct glucuronidation as the major metabolite, explaining why microsomal stability (reflective of phase I metabolism) did not translate to in vivo metabolic stability