Discovery of new vascular disrupting agents based on evolutionarily conserved drug action, pesticide resistance mutations, and humanized yeast
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 08, 2021
- Source ID
- 10.1093/genetics/iyab101
Entities
People
- Aashiq H Kachroo
- Chanjae Lee
- Edward Marcotte
- Hye Ji Cha
- Jimmy D. Gollihar
- John B. Wallingford
- Riddhiman K Garge
Organizations
- American Heart Association
- Army Research Office
- Concordia University
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Harvard Medical School
- National Institutes of Health
- Natural Sciences and Engineering Research Council
- Robert A. Welch Foundation
- University of Texas at Austin