Journal
BIOCHEMICAL PHARMACOLOGY
Volume 86, Issue 3, Pages 378-391Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.05.024
Keywords
Apoptosis; Anticancer drug; Benzimidazole Cell cycle; Checkpoint proteins; Microtubule assembly dynamics
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Funding
- Bhatnagar fellowship of the Council of Scientific and Industrial Research
- cience and Engineering Research Board
- Center of Molecular Medicine
- Department of Biotechnology, Government of India
- DAE-SRC fellowship
- Department of Atomic energy
- Government of India
- Indian Institute of Technology Bombay
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Here, we have discovered CXI-benzo-84 as a potential anticancer agent from a library of benzimidazole derivatives using cell based screening strategy. CXI-benzo-84 inhibited cell cycle progression in metaphase stage of mitosis and accumulated spindle assembly checkpoint proteins Mad2 and BubR1 on kinetochores, which subsequently activated apoptotic cell death in cancer cells. CXI-benzo-84 depolymerized both interphase and mitotic microtubules, perturbed EB1 binding to microtubules and inhibited the assembly and GTPase activity of tubulin in vitro. CXI-benzo-84 bound to tubulin at a single binding site with a dissociation constant of 1.2 +/- 0.2 mu M. Competition experiments and molecular docking suggested that CXI-benzo-84 binds to tubulin at the colchicine-site. Further, computational analysis provided a significant insight on the binding site of CXI-benzo-84 on tubulin. In addition to its potential use in cancer chemotherapy, CXI-benzo-84 may also be useful to screen colchicine-site agents and to understand the colchicine binding site on tubulin. (C) 2013 Elsevier Inc. All rights reserved.
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