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      Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

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          Abstract

          It is over 50 years since the discovery of microtubules, and they have become one of the most important drug targets for anti-cancer therapies. Microtubules are predominantly composed of the protein tubulin, which contains a number of different binding sites for small-molecule drugs. There is continued interest in drug development for compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs). This review highlights CBSIs discovered through diverse sources: from natural compounds, rational design, serendipitously and via high-throughput screening. We provide an update on CBSIs reported in the past three years and discuss the clinical status of CBSIs. It is likely that efforts will continue to develop CBSIs for a diverse set of cancers, and this review provides a timely update on recent developments.

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          Most cited references158

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          Targeting Mitosis in Cancer: Emerging Strategies.

          The cell cycle is an evolutionarily conserved process necessary for mammalian cell growth and development. Because cell-cycle aberrations are a hallmark of cancer, this process has been the target of anti-cancer therapeutics for decades. However, despite numerous clinical trials, cell-cycle-targeting agents have generally failed in the clinic. This review briefly examines past cell-cycle-targeted therapeutics and outlines how experience with these agents has provided valuable insight to refine and improve anti-mitotic strategies. An overview of emerging anti-mitotic approaches with promising pre-clinical results is provided, and the concept of exploiting the genomic instability of tumor cells through therapeutic inhibition of mitotic checkpoints is discussed. We believe this strategy has a high likelihood of success given its potential to enhance therapeutic index by targeting tumor-specific vulnerabilities. This reasoning stimulated our development of novel inhibitors targeting the critical regulators of genomic stability and the mitotic checkpoint: AURKA, PLK4, and Mps1/TTK.
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            Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint.

            Cells that cannot satisfy the spindle assembly checkpoint (SAC) are delayed in mitosis (D-mitosis), a fact that has useful clinical ramifications. However, this delay is seldom permanent, and in the presence of an active SAC most cells ultimately escape mitosis and enter the next G1 as tetraploid cells. This review defines and discusses the various factors that determine how long a cell remains in mitosis when it cannot satisfy the SAC and also discusses the cell's subsequent fate.
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              An overview of tubulin inhibitors that interact with the colchicine binding site.

              Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs.
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                Author and article information

                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                03 January 2020
                January 2020
                : 13
                : 1
                : 8
                Affiliations
                School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 Dublin, Ireland; niamh.oboyle@ 123456tcd.ie
                Author notes
                [* ]Correspondence: mclougea@ 123456tcd.ie ; Tel.: +353-1-896-2809
                Author information
                https://orcid.org/0000-0001-5660-4944
                Article
                pharmaceuticals-13-00008
                10.3390/ph13010008
                7168938
                31947889
                09dd9d6e-ceeb-4073-870d-2155c725c373
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 November 2019
                : 23 December 2019
                Categories
                Review

                anti-cancer,anti-tubulin,tubulin binding,microtubule-targeting agents,colchicine,colchicine binding site,combretastatin,ca-4,tubulin destabilizing

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