Biological characterization of an improved pyrrole-based colchicine site agent identified through structure-based design

Cristina C. Rohena, Nakul S. Telang, Chenxiao Da, April L. Risinger, James A. Sikorski, Glen E. Kellogg, John T. Gupton, Susan L. Mooberry

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


A refined model of the colchicine site on tubulin was used to design an improved analog of the pyrrole parent compound, JG- 03-14. The optimized compound, NT-7-16, was evaluated in biological assays that confirm that it has potent activities as a new colchicine site microtubule depolymerizer. NT-7-16 exhibits antiproliferative and cytotoxic activities against multiple cancer cell lines, with IC50 values of 10-16 nM, and it is able to overcome drug resistance mediated by the expression of P-glycoprotein and the bIII isotype of tubulin. NT-7-16 initiated the concentration-dependent loss of cellular microtubules and caused the formation of abnormal mitotic spindles, leading to mitotic accumulation. The direct interaction of NT-7-16 with purified tubulin was confirmed, and it was more potent than combretastatin A-4 in these assays. Binding studies verified that NT-7-16 binds to tubulin within the colchicine site. The antitumor effects of NT-7-16 were evaluated in an MDA-MB-435 xenograft model and it had excellent activity at concentrations that were not toxic. A second compound, NT-9-21, which contains dichloro moieties in place of the 3,5-dibromo substituents of NT- 7-16, had a poorer fit within the colchicine site as predicted by modeling and the Hydropathic INTeractions score. Biological evaluations showed that NT-9-21 has 10-fold lower potency than NT-7-16, confirming the modeling predictions. These studies highlight the value of the refined colchicine-site model and identify a new pyrrole-based colchicine-site agent with potent in vitro activities and promising in vivo antitumor actions.

Original languageEnglish (US)
Pages (from-to)287-296
Number of pages10
JournalMolecular pharmacology
Issue number2
StatePublished - Feb 1 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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