title: Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation.
abstract: OBJECTIVE
  The 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.
  
  
  METHODS
  Metabolic 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.
  
  
  RESULTS
  Of 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.
  
  
  CONCLUSIONS
  Rapid 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.
authors: Cancer Therapeutics Program, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Room G27e, 5117 Centre Ave, Pittsburgh, PA, 15213, USA.|Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
authors: Brian F
authors: BF
authors: Kiesel
authors: Cancer Therapeutics Program, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Room G27e, 5117 Centre Ave, Pittsburgh, PA, 15213, USA.
authors: Robert A
authors: RA
authors: Parise
authors: Cancer Therapeutics Program, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Room G27e, 5117 Centre Ave, Pittsburgh, PA, 15213, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Jianxia
authors: J
authors: Guo
authors: Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.|University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Donna M
authors: DM
authors: Huryn
authors: Cancer Therapeutics Program, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Room G27e, 5117 Centre Ave, Pittsburgh, PA, 15213, USA.|Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
authors: Paul A
authors: PA
authors: Johnston
authors: University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Raffaele
authors: R
authors: Colombo
authors: Cancer Therapeutics Program, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Room G27e, 5117 Centre Ave, Pittsburgh, PA, 15213, USA.|Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Malabika
authors: M
authors: Sen
authors: Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of California, San Francisco, CA, USA.
authors: Jennifer R
authors: JR
authors: Grandis
authors: Cancer Therapeutics Program, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Room G27e, 5117 Centre Ave, Pittsburgh, PA, 15213, USA. beumerj@gmail.com.|Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA. beumerj@gmail.com.|Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. beumerj@gmail.com.
authors: Jan H
authors: JH
authors: Beumer
authors: Cancer Therapeutics Program, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Room G27e, 5117 Centre Ave, Pittsburgh, PA, 15213, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Julie L
authors: JL
authors: Eiseman
mesh_terms: D000818:Animals; D005260:Female; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D013829:Thiadiazines / Q000493:pharmacokinetics* / Q000633:toxicity; D014230:Triazoles / Q000493:pharmacokinetics* / Q000633:toxicity; D000093242:Interleukin-6 Inhibitors
chemical_list: D050796:STAT3 Transcription Factor; D013829:Thiadiazines; D014230:Triazoles; D000093242:Interleukin-6 Inhibitors; C000619940:UPCDC-10205
keywords: IL-6; LC-MS; Pharmacokinetics; Small molecule inhibitor of STAT3