1. Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation
- Author
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Kiesel, Brian F, Parise, Robert A, Guo, Jianxia, Huryn, Donna M, Johnston, Paul A, Colombo, Raffaele, Sen, Malabika, Grandis, Jennifer R, Beumer, Jan H, and Eiseman, Julie L
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Orphan Drug ,Infectious Diseases ,Animals ,Female ,Interleukin-6 ,Mice ,Microsomes ,Liver ,STAT3 Transcription Factor ,Thiadiazines ,Triazoles ,Pharmacokinetics ,Small molecule inhibitor of STAT3 ,IL-6 ,LC-MS ,Pharmacology and Pharmaceutical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Pharmacology and pharmaceutical sciences - Abstract
PurposeThe oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) promotes gene transcription involved in cancer, and its activation by IL-6 is found in head and neck squamous cell carcinoma. Four triazolothiadizine STAT3 pathway inhibitors were evaluated to prioritize a single compound for in vivo examination.MethodsMetabolic stability in mouse liver microsome incubation was used to evaluate four triazolothiadizine analogues, and UPCDC-10205 was administered to mice IV as single or multiple doses to evaluate toxicity. Single-dose pharmacokinetics (PK), bioavailability and metabolism were studied after IV 4 mg/kg, PO 4 mg/kg, or PO 30 mg/kg suspension in 1% carboxymethyl cellulose. Mice were euthanized between 5 min to 24 h after dosing, and plasma and tissues were analyzed by LC-MS. Non-compartmental PK parameters were determined.ResultsOf the four triazolothiadizine analogues evaluated, UPCDC-10205 was metabolically most stable. The maximum soluble dose of 4 mg/kg in 10% Solutol™ was not toxic to mice after single and multiple doses. PK analysis showed extensive tissue distribution and rapid plasma clearance. Bioavailability was ~5%. A direct glucuronide conjugate was identified as the major metabolite which was recapitulated in vitro.ConclusionsRapid clearance of UPCDC-10205 was thought to be the result of phase II metabolism despite its favorable stability in a phase I in vitro metabolic stability assay. The direct glucuronidation explains why microsomal stability (reflective of phase I metabolism) did not translate to in vivo metabolic stability. UPCDC-10205 did not demonstrate appropriate exposure to support efficacy studies in the current formulation.
- Published
- 2016