Structure-based discovery of a boronic acid bioisostere of combretastatin A-4

Yali Kong, Jolanta Grembecka, Michael C. Edler, Ernest Hamel, Susan L. Mooberry, Michal Sabat, Jayson Rieger, Milton L. Brown

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61 Scopus citations

Abstract

Targeting the microtubule system represents an attractive strategy for the development of anticancer agents. In this study, we report a class of combretastatin A-4 (CA-4) analogs derivatized with a boronic acid moiety replacing the hydroxyl group on the C-ring of CA-4. Docking studies of the X-ray structures of our aryl-boronic analogs onto an X-ray structure of the α,β-tubulin heterodimer suggested that cis-6 was a potent inhibitor of the colchicine binding. The model indicated that there would be strong hydrogen bonding between the boronic acid moiety and Thr-179 and Val-181 of α-tubulin. We demonstrate that the cis-6 boronic acid bioisostere of CA-4: (1) inhibits tubulin assembly, (2) competitively displaces colchicine, and (3) is a low-nanomolar inhibitor of human cancer cell lines. We present this isostere as a class of potent analogs of CA-4.

Original languageEnglish (US)
Pages (from-to)1007-1014
Number of pages8
JournalChemistry and Biology
Volume12
Issue number9
DOIs
Publication statusPublished - Sep 1 2005

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Kong, Y., Grembecka, J., Edler, M. C., Hamel, E., Mooberry, S. L., Sabat, M., ... Brown, M. L. (2005). Structure-based discovery of a boronic acid bioisostere of combretastatin A-4. Chemistry and Biology, 12(9), 1007-1014. https://doi.org/10.1016/j.chembiol.2005.06.016