CB694, a novel antimitotic with antitumor activities

Weiderhold, Kimberly N.; Randall-Hlubek, Deborah A.; Polin, Lisa; Hamel, Ernest; Mooberry, Susan L.

doi:10.1002/ijc.21424

Cited by 18 publications

(19 citation statements)

References 26 publications

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“…However, there is some discrepancy with regard to the ability of microtubule-destabilizing agents to cause formation of these abnormal mitotic structures between our findings (Fig. 3B) (Tinley et al, 2003a;Weiderhold et al, 2006) and others (Chen and Horwitz, 2002). From our jpet.aspetjournals.org observations in this study and others, we have found that there is a very small concentration window where multiple spindles can be observed upon treatment of cells with microtubule-destabilizing agents because of the inherent nature of these compounds to inhibit microtubule polymerization and enhance microtubule depolymerization, thus leading ultimately to a loss of all cellular microtubules.…”

Section: Discussioncontrasting

confidence: 78%

ELR510444, A Novel Microtubule Disruptor with Multiple Mechanisms of Action

Risinger¹,

Westbrook²,

Encinas³

et al. 2010

J Pharmacol Exp Ther

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Although several microtubule-targeting drugs are in clinical use, there remains a need to identify novel agents that can overcome the limitations of current therapies, including acquired and innate drug resistance and undesired side effects. In this study, we show that ELR510444 has potent microtubuledisrupting activity, causing a loss of cellular microtubules and the formation of aberrant mitotic spindles and leading to mitotic arrest and apoptosis of cancer cells. ELR510444 potently inhibited cell proliferation with an IC 50 value of 30.9 nM in MDA-MB-231 cells, inhibited the rate and extent of purified tubulin assembly, and displaced colchicine from tubulin, indicating that the drug directly interacts with tubulin at the colchicine-binding site. ELR510444 is not a substrate for the P-glycoprotein drug transporter and retains activity in ␤III-tubulin-overexpressing cell lines, suggesting that it circumvents both clinically relevant mechanisms of drug resistance to this class of agents. Our data show a close correlation between the concentration of ELR510444 required for inhibition of cellular proliferation and that required to cause significant loss of cellular microtubule density, consistent with its activity as a microtubule depolymerizer. ELR510444 also shows potent antitumor activity in the MDA-MB-231 xenograft model with at least a 2-fold therapeutic window. Studies in tumor endothelial cells show that a low concentration of ELR510444 (30 nM) rapidly alters endothelial cell shape, similar to the effect of the vascular disrupting agent combretastatin A4. These results suggest that ELR510444 is a novel microtubule-disrupting agent with potential antivascular effects and in vivo antitumor efficacy.

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Section: Discussioncontrasting

confidence: 78%

ELR510444, A Novel Microtubule Disruptor with Multiple Mechanisms of Action

Risinger¹,

Westbrook²,

Encinas³

et al. 2010

J Pharmacol Exp Ther

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“…The 1.7 RR value indicates that JG-03-14 is a poor substrate for transport by Pgp. Paclitaxel (Taxol), a well-known substrate for Pgp, has an RR value in these cell lines of 827 to 4050 (Tinley et al, 2003b;Weiderhold et al, 2006). Further studies to evaluate the ability of JG-03-14 to be a substrate for Pgp-mediated transport were conducted using the NCI/ADR cell line.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to disrupting interphase microtubules, microtubule-depolymerizing agents cause the formation of abnormal mitotic spindles (Tinley et al, 2003a;Weiderhold et al, 2006). The effects of JG-03-14 on mitotic spindles were evaluated in HeLa cells.…”

Section: Jg-03-14 Inhibits the Growth Of Cancer Cell Lines And Evadesmentioning

confidence: 99%

“…An abnormal, wide G 1 peak was observed in cells treated with 50 and 60 nM JG-03-14. This peak has been referred to as an aneuploid G 1 peak, and it occurs in cells treated with low concentrations of microtubule stabilizers (Chen and Horwitz, 2002) and some microtubule-depolymerizing agents (Weiderhold et al, 2006). At slightly higher concentrations, there was no evidence of any G 1 peak, and most of the cells were in the G 2 /M phase of the cell cycle.…”

Section: A New Tubulin-binding Tetrasubstituted Brominated Pyrrolementioning

confidence: 99%

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Identification and Characterization of a New Tubulin-Binding Tetrasubstituted Brominated Pyrrole

et al. 2007

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We studied the mechanism of action of 3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester and found that it is a potent microtubule depolymerizer. JG-03-14 caused a dose-dependent loss of cellular microtubules, formation of aberrant mitotic spindles, accumulation of cells in the G 2 /M phase of the cell cycle, and Bcl-2 phosphorylation. These events culminated in the initiation of apoptosis, as evidenced by the caspase 3-dependent cleavage of poly-(ADP-ribose) polymerase (PARP). JG-03-14 has antiproliferative activity against a wide range of cancer cell lines, with an average IC 50 value of 62 nM, and it is a poor substrate for transport by P-glycoprotein. JG-03-14 inhibited the polymerization of purified tubulin in vitro, consistent with a direct interaction between the compound and tubulin. JG-03-14 potently inhibited the binding of [ 3 H]colchicine to tubulin, suggesting that it bound to tubulin at a site overlapping the colchicine site. JG-03-14 had antitumor effects in the PC3 xenograft model, in which it caused greater than 50% reduction in tumor burden after 14 days of treatment. Molecular modeling studies indicated that the dimethoxyphenyl group of JG-03-14 occupies a space similar to that of the trimethoxyphenyl group of colchicine. However, the 2,3,5-trisubstituted pyrrole group, which is connected to the dimethoxyphenyl moiety, interacted with both ␣ and ␤ tubulin in space not shared with colchicine, suggesting significant differences compared with colchicine in the mechanism of binding to tubulin. Our results suggest that this tetrasubstituted pyrrole represents a new, biologically active chemotype for the colchicine site on tubulin.Microtubules are cellular structures that play a central role in metabolism, intracellular transport, and cell division. A wide range of chemicals have been identified that interrupt microtubule function. These compounds can be divided into microtubule stabilizers and microtubule depolymerizers. Microtubule stabilizers include paclitaxel, discodermolide, the epothilones, and the laulimalides. Microtubule stabilizers cause an increase in the density of cellular microtubules, and they stimulate the assembly of purified tubulin. In contrast, microtubule depolymerizers cause a loss of cellular microtubules, and they inhibit the assembly of purified tubulin. Microtubule depolymerizing compounds can be further subdivided into those that bind to tubulin within the colchicine site and those that bind within the vinca domain. Agents acting upon the colchicine site include 2ME2, combretastatin A-4, and podophyllotoxin. The phenotypic effects of microtubule stabilizing and depolymerizing agents are quite disparate when they are used at high concentrations in cells, but at their lowest antiproliferative concentrations, both classes of agents inhibit microtubule dynamics (Jordan and Wilson, 2004). In due course, inhibition of microtubule dynamics is believed to hinder the normal function of the mitotic spindle,

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“…21,22 On the other hand, a novel microtubule depolymerizing piperazine derivative, 1-(5-chloro-2-methoxybenzoyl)-4-(3-chlorophenyl) piperazine, caused inhibition of proliferation of a wide range of cancer cell lines including a multidrug-resistant cell line, with an average IC50 of 85 nM. 23 These results once again highlighted that piperazine core was an important backbone and prompted us to design some active molecules with piperazine nucleus.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Azole-containing Piperazine Derivatives and Evaluation of their Antibacterial, Antifungal and Cytotoxic Activities

Gan¹,

Fang²,

Zhou³

2010

Bulletin of the Korean Chemical Society

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A series of azole-containing piperazine derivatives have been designed and synthesized. The obtained compounds were investigated in vitro for their antibacterial, antifungal and cytotoxic activities. The preliminary results showed that most compounds exhibited moderate to significant antibacterial and antifungal activities in vitro. 1-(4-((4-chlorophenyl) (phenyl)methyl)piperazin-1-yl)-2-(1H-imidazol-1-yl)ethanone and 1-(4-((4-Chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-(2-phenyl-1H-imidazol-1-yl)ethanone gave remarkable and broad-spectrum antimicrobial efficacy against all tested strains with MIC values ranging from 3.1 to 25 μg/mL, and exhibited comparable activities to the standard drugs chloramphenicol and fluconazole in clinic. Moreover, 2-((4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)methyl)-1H-benzo [d]imidazole was found to be the most effective in vitro against the PC-3 cell line, reaching growth inhibition values (36.4, 60.1 and 76.5%) for each tested concentration: 25 μM, 50 μΜ and 100 μM in dose-dependent manner. The results also showed that the azole ring had noticeable effect on their antimicrobial and cytotoxic activities, and imidazole and benzimidazole moiety were much more favourable to biological activity than 1,2,4-triazole.

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CB694, a novel antimitotic with antitumor activities

Cited by 18 publications

References 26 publications

ELR510444, A Novel Microtubule Disruptor with Multiple Mechanisms of Action

ELR510444, A Novel Microtubule Disruptor with Multiple Mechanisms of Action

Identification and Characterization of a New Tubulin-Binding Tetrasubstituted Brominated Pyrrole

Synthesis of Azole-containing Piperazine Derivatives and Evaluation of their Antibacterial, Antifungal and Cytotoxic Activities

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