Discovery of novel tubulin inhibitors targeting the colchicine binding site via virtual screening, structural optimization and antitumor evaluation

Liu, Wei; Jia, Hairui; Guan, Minghao; Cui, Minxuan; Lan, Zhuxuan; He, Youyou; Guo, Zhongjie; Jiang, Ru; Dong, Guoqiang; Wang, Shengzheng

doi:10.1016/j.bioorg.2021.105486

Cited by 12 publications

(13 citation statements)

References 40 publications

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“…The synthetic procedure was depicted in Scheme 1 . Accordingly to our previous report, 5-methoxyisatin ( A1 ) and 3′,4′-(methylenedioxy)acetophenone ( B1 ) were dissolved in ethanol solvent and refluxed to obtain the intermediate C1 34 . In DCM solvent, intermediate C1 was refluxed with SOCl 2 to afford acid chloride derivative.…”

Section: Resultsmentioning

confidence: 99%

“…The tubulin inhibition activity was performed according to our previous reports 34 , 35 . Colchicine was used as the positive control.…”

Section: Resultsmentioning

confidence: 99%

“…To clarify the binding mode of G13 with tubulin, molecular docking using Glide within Schrodinger software was performed according to our previous report 34 . As depicted in Figure 4(C) , G13 was observed to be well-fitted into the colchicine binding site.…”

Section: Resultsmentioning

confidence: 99%

“…In our previous study, structure based virtual screening against colchicine binding site was performed to indentify 2-aryl-4-amide-quinoline hit 9 ( Figure 2(A) ) displayed moderate tubulin polymerisation inhibitory activity (IC 50 = 25.3 μM) and broad-spectrum in vitro antiproliferative activity (IC 50 values: 49.1 μM∼70.1 μM) 34 . After the preliminary structural optimisation, analogue E27 ( Figure 2(A) ) was identified to display improved enzymatic inhibition activity (IC 50 = 16.1 μM) and antitumour activity (IC 50 values: 7.81 μM∼10.36 μM).…”

Section: Introductionmentioning

confidence: 99%

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Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation

Liu

Guo

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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The colchicine binding site of tubulin is a promising target for discovering novel antitumour agents. Previously, we identified 2-aryl-4-amide-quinoline derivatives displayed moderate tubulin polymerisation inhibitory activity and broad-spectrum in vitro antitumour activity. In this study, structure based rational design and systematic structural optimisation were performed to obtain analogues C1∼J2 bearing diverse substituents and scaffolds. Among them, analogue G13 bearing a hydroxymethyl group displayed good tubulin polymerisation inhibitory activity (IC 50 = 13.5 μM) and potent antiproliferative activity (IC 50 values: 0.65 μM∼0.90 μM). G13 potently inhibited the migration and invasion of MDA-MB-231 cells, and displayed potent antiangiogenic activity. It efficiently increased intracellular ROS level and decreased MMP in cancer cells, and obviously induced the fragmentation and disassembly of the microtubules network. More importantly, G13 exhibited good in vivo antitumour efficacy in MDA-MB-231 xenograft model (TGI = 38.2%; i.p., 30 mg/kg).

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Section: Resultsmentioning

confidence: 99%

“…The tubulin inhibition activity was performed according to our previous reports 34 , 35 . Colchicine was used as the positive control.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation

Liu

Guo

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Microtubule-destabilizing agents, such as vincristine, combretastatin A4, ABT-751, or colchicine, have been employed for the treatment of different tumor types [ 31 , 38 , 39 ]. These compounds impair the microtubule network by disrupting their assembly, produce a G2/M cell cycle arrest, and induce apoptosis [ 14 , 38 , 39 , 40 , 41 , 42 ]. These effects are also produced by our previously described MDS [ 14 ] and by PILA9 .…”

Section: Discussionmentioning

confidence: 99%

Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells

Ovejero-Sánchez

Asensio-Juárez

González

et al. 2022

IJMS

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Ovarian cancer (OC) is one of the most common gynecologic neoplasia and has the highest mortality rate, which is mainly due to late-stage diagnosis and chemotherapy resistance. There is an urgent need to explore new and better therapeutic strategies. We have previously described a family of Microtubule Destabilizing Sulfonamides (MDS) that does not trigger multidrug-mediated resistance in OC cell lines. MDS bind to the colchicine site of tubulin, disrupting the microtubule network and causing antiproliferative and cytotoxic effects. In this work, a novel microtubule-destabilizing agent (PILA9) was synthetized and characterized. This compound also inhibited OC cell proliferation and induced G2/M cell cycle arrest and apoptosis. Interestingly, PILA9 was significantly more cytotoxic than MDS. Here, we also analyzed the effect of these microtubule-destabilizing agents (MDA) in combination with Panobinostat, a pan-histone deacetylase inhibitor. We found that Panobinostat synergistically enhanced MDA-cytotoxicity. Mechanistically, we observed that Panobinostat and MDA induced α-tubulin acetylation and that the combination of both agents enhanced this effect, which could be related to the observed synergy. Altogether, our results suggest that MDA/Panobinostat combinations could represent new therapeutic strategies against OC.

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Discovery of novel microtubule stabilizers targeting taxane binding site by applying molecular docking, molecular dynamics simulation, and anticancer activity testing

Zhang

Mao

et al. 2022

Bioorganic Chemistry

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Discovery of novel tubulin inhibitors targeting the colchicine binding site via virtual screening, structural optimization and antitumor evaluation

Cited by 12 publications

References 40 publications

Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation

Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation

Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells

Discovery of novel microtubule stabilizers targeting taxane binding site by applying molecular docking, molecular dynamics simulation, and anticancer activity testing

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