4-Bromophenylhydrazinyl benzenesulfonylphenylureas as indoleamine 2,3-dioxygenase inhibitors with in vivo target inhibition and anti-tumor efficacy

Shu Yu Lin, Teng Kuang Yeh, Jen Shin Song, Ming Shiu Hung, Ming Fu Cheng, Fang Yu Liao, An Shiou Li, Shu Ying Cheng, Li Mei Lin, Chun Hsien Chiu, Mine Hsine Wu, Yi Jyun Lin, Wenchi Hsiao, Manwu Sun, Yi Hsin Wang, Chin Hsiang Huang, Ya Chu Tang, Hsin Huei Chang, Zih Ting Huang, Yu Sheng ChaoChuan Shih, Shiow Lin Pan, Su Ying Wu, Ching Chuan Kuo, Shau Hua Ueng

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Indoleamine 2,3-dioxygenase is a heme-containing enzyme implicated in the down regulation of the anti-tumor immune response, and considered a promising anti-cancer drug target. Several pharmaceutical companies, including Pfizer, Merck, and Bristol-Myers Squibb, are known to be in pursuit of IDO inhibitors, and Incyte recently reported good results in the phase II clinical trial of the IDO inhibitor Epacadostat. In previous work, we developed a series of IDO inhibitors based on a sulfonylhydrazide core structure, and explored how they could serve as potent IDO inhibitors with good drug profiles. Herein, we disclose the development of the 4-bromophenylhydrazinyl benzenesulfonylphenylurea 5k, a potent IDO inhibitor which demonstrated 25% tumor growth inhibition in a murine CT26 syngeneic model on day 18 with 100 mg/kg oral administration twice daily, and a 30% reduction in tumor weight. Pharmacodynamic testing of 5k found it to cause a 25% and 21% reduction in kyn/trp ratio at the plasma and tumor, respectively. In the CT26 tumor model, 5k was found to slightly increase the percentage of CD3+ T cells and lymphocyte responsiveness, indicating that 5k may have potential in modulating anti-tumor immunity. These data suggest 5k to be worthy of further investigation in the development of anti-tumor drugs.

Original languageEnglish
Pages (from-to)600-607
Number of pages8
JournalBioorganic Chemistry
Volume77
DOIs
Publication statusPublished - Apr 1 2018

Keywords

  • 4-Bromophenylhydrazinyl benzenesulfonylphenylurea
  • Anti-tumor
  • In vivo target inhibition
  • Indoleamine 2,3-dioxygenase
  • Inhibitor
  • Kynurenine
  • Tryptophan

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Lin, S. Y., Yeh, T. K., Song, J. S., Hung, M. S., Cheng, M. F., Liao, F. Y., Li, A. S., Cheng, S. Y., Lin, L. M., Chiu, C. H., Wu, M. H., Lin, Y. J., Hsiao, W., Sun, M., Wang, Y. H., Huang, C. H., Tang, Y. C., Chang, H. H., Huang, Z. T., ... Ueng, S. H. (2018). 4-Bromophenylhydrazinyl benzenesulfonylphenylureas as indoleamine 2,3-dioxygenase inhibitors with in vivo target inhibition and anti-tumor efficacy. Bioorganic Chemistry, 77, 600-607. https://doi.org/10.1016/j.bioorg.2018.02.010