Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation.

Abstract

PURPOSE:

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: Brian F Kiesel, Robert A Parise, Jianxia Guo, Donna M Huryn, Paul A Johnston, Raffaele Colombo, Malabika Sen, Jennifer R Grandis, Jan H Beumer, Julie L Eiseman
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 78 Issue 6 Pg. 1225-1235 (Dec 2016) ISSN: 1432-0843 [Electronic] Germany
• PMID: 27778071 (Publication Type: Journal Article)

Chemical References

• Interleukin-6
• STAT3 Transcription Factor
• Thiadiazines
• Triazoles
• UPCDC-10205

Topics

• Animals
• Female
• Interleukin-6 (antagonists & inhibitors)
• Mice
• Microsomes, Liver (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors)
• Thiadiazines (pharmacokinetics, toxicity)
• Triazoles (pharmacokinetics, toxicity)