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

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


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
Issue number9
StatePublished - Sep 2005

ASJC Scopus subject areas

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


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