Structure of 4′-demethylepipodophyllotoxin in complex with tubulin provides a rationale for drug design

Li, Niu; Wang, Yuxi; Wang, Chengdi; Wang, Yanyan; Jiang, Xiaohua; Ma, Lingling; Wu, Chengyong; Yu, Yamei; Chen, Qiang

doi:10.1016/j.bbrc.2017.08.125

Cited by 16 publications

(5 citation statements)

References 22 publications

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“…All of them were shown as effective tools to develop novel inhibitors targeting the various binding sites of proteins, including the CBS of the tubulin. This is due to the availability of the multiple X-ray structures of tubulin-ligand complexes, which provide important information about the conformational changes in the tubulin molecule and interactions between various functional groups of ligands and amino acids of the CBS [57][58][59][60]. The use of the in silico approach significantly reduces the cost to develop novel drugs and allows the negative selection of non-effective molecules at the early stage of drug discovery.…”

Section: Discussionmentioning

confidence: 99%

Computational-Based Discovery of the Anti-Cancer Activities of Pyrrole-Based Compounds Targeting the Colchicine-Binding Site of Tubulin

et al. 2022

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Despite the tubulin-binding agents (TBAs) that are widely used in the clinic for cancer therapy, tumor resistance to TBAs (both inherited and acquired) significantly impairs their effectiveness, thereby decreasing overall survival (OS) and progression-free survival (PFS) rates, especially for the patients with metastatic, recurrent, and unresectable forms of the disease. Therefore, the development of novel effective drugs interfering with the microtubules’ dynamic state remains a big challenge in current oncology. We report here about the novel ethyl 2-amino-1-(furan-2-carboxamido)-5-(2-aryl/tert-butyl-2-oxoethylidene)-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylates (EAPCs) exhibiting potent anti-cancer activities against the breast and lung cancer cell lines in vitro. This was due to their ability to inhibit tubulin polymerization and induce cell cycle arrest in M-phase. As an outcome, the EAPC-treated cancer cells exhibited a significant increase in apoptosis, which was evidenced by the expression of cleaved forms of PARP, caspase-3, and increased numbers of Annexin-V-positive cells. By using the in silico molecular modeling methods (e.g., induced-fit docking, binding metadynamics, and unbiased molecular dynamics), we found that EAPC-67 and -70 preferentially bind to the colchicine-binding site of tubulin. Lastly, we have shown that the EAPCs indicated above and colchicine utilizes a similar molecular mechanism to inhibit tubulin polymerization via targeting the T7 loop in the β-chain of tubulin, thereby preventing the conformational changes in the tubulin dimers required for their polymerization. Collectively, we identified the novel and potent TBAs that bind to the colchicine-binding site and disrupt the microtubule network. As a result of these events, the compounds induced a robust cell cycle arrest in M-phase and exhibited potent pro-apoptotic activities against the epithelial cancer cell lines in vitro.

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Section: Discussionmentioning

confidence: 99%

Computational-Based Discovery of the Anti-Cancer Activities of Pyrrole-Based Compounds Targeting the Colchicine-Binding Site of Tubulin

et al. 2022

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“…16 ). Three of these compounds are microtubule inhibitors: 4’-Demethylepipodophyllotoxin (a potent inhibitor of microtubule assembly) 21 , H-Cys(Trt)-OH (a specific inhibitor of Eg5 that inhibits Eg5-driven microtubule sliding velocity in a reversible fashion) 22 , 2-Methoxyestradiol (an inhibitor of polymerization of tubulin) 23 , and the other one is myosin II inhibitor, Blebbistatin 24 ( Supplementary Fig. 16 ).…”

Section: Resultsmentioning

confidence: 99%

Rock inhibitors target SRSF2 leukemia by disrupting cell mitosis and nuclear morphology

Fleisher

Grosheva

et al. 2022

Preprint

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Spliceosome machinery mutations are common early mutations in myeloid malignancies, however effective targeted therapies against them are still lacking. In the current study, we used an in vitro high-throughput drug screen among four different isogenic cell lines and identified ROCK inhibitors (ROCKi) as selective inhibitors of SRSF2 mutants. ROCKi targeted SRSF2 Mut primary human samples in a xenografts model and were not toxic to mice nor human cells. ROCKi induced mitotic catastrophe through their apparent effects on microtubules and nuclear organization. Transmission electron microscopy revealed that SRSF2 mutations induce deep nuclear indentation and segmentation, driven by microtubule-rich cytoplasmic intrusions, which were exacerbated by ROCKi. The severe nuclear deformation driven by the combination of SRSF2 Mut and ROCKi prevent cells from completing mitosis. These findings shed light on new ways to target SRSF2 and on the role of the microtubule system in SRSF2 Mut cells.

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“…Since L1 potently competes with colchicine (figure 4), we speculate that the benzodioxole group of L1 also occupies the hydrophobic pocket of β-tubulin. However, in the crystal structure of the α /β-tubulin-RB3-TTL complex with podophyllotoxin or its analogue, which have both trimethoxyphenyl and benzodioxole moieties, the position of the benzodioxole matches to the methoxytropolone C ring of colchicine [34], not the aforementioned hydrophobic pocket, suggesting that benzodioxole can fit to the colchicine-binding sites in multiple configurations. Thus, benzodioxole is a versatile chemical group for targeting the colchicine-binding site of β-tubulin.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel microtubule inhibitors effective in fission yeast and human cells and their effects on breast cancer cell lines

Morishita

Nurse

2021

Open Biol.

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Microtubules are critical for a variety of cellular processes such as chromosome segregation, intracellular transport and cell shape. Drugs against microtubules have been widely used in cancer chemotherapies, though the acquisition of drug resistance has been a significant issue for their use. To identify novel small molecules that inhibit microtubule organization, we conducted sequential phenotypic screening of fission yeast and human cells. From a library of diverse 10 371 chemicals, we identified 11 compounds that inhibit proper mitotic progression both in fission yeast and in HeLa cells. An in vitro assay revealed that five of these compounds are strong inhibitors of tubulin polymerization. These compounds directly bind tubulin and destabilize the structures of tubulin dimers. We showed that one of the compounds, L1, binds to the colchicine-binding site of microtubules and exhibits a preferential potency against a panel of human breast cancer cell lines compared with a control non-cancer cell line. In addition, L1 overcomes cellular drug resistance mediated by βIII tubulin overexpression and has a strong synergistic effect when combined with the Plk1 inhibitor BI2536. Thus, we have established an economically effective drug screening strategy to target mitosis and microtubules, and have identified a candidate compound for cancer chemotherapy.

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Structure of 4′-demethylepipodophyllotoxin in complex with tubulin provides a rationale for drug design

Cited by 16 publications

References 22 publications

Computational-Based Discovery of the Anti-Cancer Activities of Pyrrole-Based Compounds Targeting the Colchicine-Binding Site of Tubulin

Computational-Based Discovery of the Anti-Cancer Activities of Pyrrole-Based Compounds Targeting the Colchicine-Binding Site of Tubulin

Rock inhibitors target SRSF2 leukemia by disrupting cell mitosis and nuclear morphology

Identification of novel microtubule inhibitors effective in fission yeast and human cells and their effects on breast cancer cell lines

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