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

Autor:	Garge RK; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA., Cha HJ; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA., Lee C; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA., Gollihar JD; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.; US Army Research Laboratory-South, Austin, TX 78758, USA., Kachroo AH; The Department of Biology, Centre for Applied Synthetic Biology, Concordia University, Montreal, QC H4B 1R6, Canada., Wallingford JB; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA., Marcotte EM; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
Jazyk:	angličtina
Zdroj:	Genetics [Genetics] 2021 Aug 26; Vol. 219 (1).
DOI:	10.1093/genetics/iyab101
Abstrakt:	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. (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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