Discovery of new vascular disrupting agents based on evolutionarily conserved drug action, pesticide resistance mutations, and humanized yeast

Riddhiman K. Garge, Hye Ji Cha, Chanjae Lee, Jimmy D. Gollihar, Aashiq H. Kachroo, John B. Wallingford, Edward M. Marcotte

Research output: Contribution to journalArticlepeer-review

Abstract

Thiabendazole (TBZ) is an FDA-approved benzimidazole widely used for its antifungal and antihelminthic properties. We showed previously that TBZ is also a potent vascular disrupting agent and inhibits angiogenesis at the tissue level by dissociating vascular endothelial cells in newly formed blood vessels. Here, we uncover TBZ's molecular target and mechanism of action. Using human cell culture, molecular modeling, and humanized yeast, we find that TBZ selectively targets only 1 of 9 human β-tubulin isotypes (TUBB8) to specifically disrupt endothelial cell microtubules. By leveraging epidemiological pesticide resistance data and mining chemical features of commercially used benzimidazoles, we discover that a broader class of benzimidazole compounds, in extensive use for 50 years, also potently disrupt immature blood vessels and inhibit angiogenesis. Thus, besides identifying the molecular mechanism of benzimidazole-mediated vascular disruption, this study presents evidence relevant to the widespread use of these compounds while offering potential new clinical applications.

Original languageEnglish (US)
JournalGenetics
Volume219
Issue number1
DOIs
StatePublished - Aug 26 2021

Keywords

  • angiogenesis
  • epidemiology
  • evolution
  • humanized yeast
  • phenologs
  • systems biology
  • vascular disrupting agents

ASJC Scopus subject areas

  • Genetics

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