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

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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

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Abbreviations

CMC:

Carboxymethyl cellulose

LC–MS/MS:

Liquid chromatography-tandem mass spectrometry

PK:

Pharmacokinetics

UGT:

UDP-glucuronosyltransferase

HCS:

High-content screening

AUC:

Area under the curve

C max :

Maximum peak concentration

T max :

Time of maximum concentration

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Acknowledgements

This Project has been funded, in part, with Federal Funds from the National Cancer Institute, National Institutes of Health, under Contract No. HSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This work was supported by the NExT-CBC Project ID #1015, S08-221 Task Order 6 ‘‘STAT3 Pathway Inhibitor HCS’’ (Grandis, PI), NCI Chemical Biology Consortium, Pittsburgh Specialized Application Center (PSAC; Lazo and Johnston co-PIs), and University of Pittsburgh Chemical Diversity Center (Huryn, PI). The Project was also supported, in part, by funds from the American Cancer Society (Grandis) and a Head and Neck Spore P50 award (Grandis, CA097190). This Project was funded in the National Cancer Institute, National Institutes of Health, under Chemical Biology Consortium Contract No. HSN261200800001E. We are grateful for scientific contributions from Peter Wipf, Matthew LaPorte, Atefeh Garzan, Mary Liang, Vsevolod A. Peshkov, and Zhuzhu Wang. This Project used the UPCI Animal Facility (AF) and Clinical Pharmacokinetic and Pharmacodynamic Facility (CPPF) and was supported in part by Award P30CA047904.

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Authors and Affiliations

  1. Cancer Therapeutics Program, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Room G27e, 5117 Centre Ave, Pittsburgh, PA, 15213, USA

    Brian F. Kiesel, Robert A. Parise, Jianxia Guo, Paul A. Johnston, Malabika Sen, Jan H. Beumer & Julie L. Eiseman

  2. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    Brian F. Kiesel, Donna M. Huryn, Paul A. Johnston & Jan H. Beumer

  3. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Jianxia Guo & Julie L. Eiseman

  4. University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA, USA

    Donna M. Huryn & Raffaele Colombo

  5. Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Malabika Sen

  6. Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of California, San Francisco, CA, USA

    Jennifer R. Grandis

  7. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Jan H. Beumer

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  1. Brian F. Kiesel
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  2. Robert A. Parise
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Correspondence to Jan H. Beumer.

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Kiesel, B.F., Parise, R.A., Guo, J. et al. Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation. Cancer Chemother Pharmacol 78, 1225–1235 (2016). https://doi.org/10.1007/s00280-016-3181-9

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  • DOI: https://doi.org/10.1007/s00280-016-3181-9

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