Structural Basis of Microtubule Stabilization by Laulimalide and Peloruside A

Prota, A.E.; Bargsten, Katja; Northcote, Peter T.; Marsh, M.; Altmann, Karl‐Heinz; Miller, John H.; Dı́az, José Fernando; Steinmetz, Michel O.

doi:10.1002/ange.201307749

Cited by 124 publications

(29 citation statements)

References 20 publications

(33 reference statements)

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“…This site is located on the exterior of the microtubule. 11 Recently, Prota et al 12 demonstrated that maytansine binds to a different site on β -tubulin, and they named this the maytansine site. Maytansine, rhizoxin F, and a polyketide PM060184, initially isolated from the marine sponge Lithoplocamia lithistoides , bind within this newly characterized site, occupancy of which prevents the addition of new subunits to the plus ends of microtubules, resulting in microtubule depolymerization.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Preclinical Evaluation of 4-Substituted-5-methyl-furo[2,3-d]pyrimidines as Microtubule Targeting Agents That Are Effective against Multidrug Resistant Cancer Cells

et al. 2016

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The design, synthesis, and biological evaluations of eight 4-substituted 5-methyl-furo[2,3-d]pyrimidines are reported. Synthesis involved N4-alkylation of N-aryl-5-methylfuro[2,3-d]pyrimidin-4-amines, obtained from Ullmann coupling of 4-amino-5-methylfuro[2,3-d]pyrimidine and appropriate aryl iodides. Compounds 3, 4, and 9 showed potent microtubule depolymerizing activities, while compounds 6–8 had slightly lower potency. Compounds 4, 6, 7, and 9 inhibited tubulin assembly with IC50 values comparable to that of combretastatin A-4 (CA-4). Compounds 3, 4, and 6–9 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that can limit the efficacy of paclitaxel, docetaxel, and the vinca alkaloids. In the NCI 60-cell line panel, compound 3 exhibited GI50 values less than 10 nM in 47 of the cell lines. In an MDA-MB-435 xenograft model, compound 3 had statistically significant antitumor effects. The biological effects of 3 identify it as a novel, potent microtubule depolymerizing agent with antitumor activity.

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Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Preclinical Evaluation of 4-Substituted-5-methyl-furo[2,3-d]pyrimidines as Microtubule Targeting Agents That Are Effective against Multidrug Resistant Cancer Cells

et al. 2016

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“…In addition to the inhibition of tubulin polymerization, it inhibits tubulin‐dependent GTP hydrolysis and the binding of vinblastine, maytansine, and vincristine to tubulin, although its binding site on tubulin is different from that of the vinca alkaloids . The tubulin‐binding sites of colchicine, taxol, vinblastine, rhizoxin F, and maytansine are discussed by Prota et al . and in the commentary by Field et al …”

Section: Mollusk‐derived Anticancer Agentsmentioning

confidence: 99%

“…Laulimalide is active in P‐gp overexpressing cancer cells and against cell lines resistant to paclitaxel or epothilones . It has a unique binding site located on two adjacent β‐tubulin units between tubulin protofilaments of a microtubule . In addition, although laulimalide is a microtubule stabilizer as are the plant‐derived metabolites taccalonolide and paclitaxel, laulimalide causes the formation of aberrant, but structurally distinct mitotic spindles in contrast to the effects induced by the other two molecules .…”

Section: Mollusk‐derived Anticancer Agentsmentioning

confidence: 99%

Marine Mollusk‐Derived Agents with Antiproliferative Activity as Promising Anticancer Agents to Overcome Chemotherapy Resistance

Ciavatta

Lefranc

Carbone

et al. 2016

Medicinal Research Reviews

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The chemical investigation of marine mollusks has led to the isolation of a wide variety of bioactive metabolites, which evolved in marine organisms as favorable adaptations to survive in different environments. Most of them are derived from food sources, but they can be also biosynthesized de novo by the mollusks themselves, or produced by symbionts. Consequently, the isolated compounds cannot be strictly considered as “chemotaxonomic markers” for the different molluscan species. However, the chemical investigation of this phylum has provided many compounds of interest as potential anticancer drugs that assume particular importance in the light of the growing literature on cancer biology and chemotherapy. The current review highlights the diversity of chemical structures, mechanisms of action, and, most importantly, the potential of mollusk‐derived metabolites as anticancer agents, including those biosynthesized by mollusks and those of dietary origin. After the discussion of dolastatins and kahalalides, compounds previously studied in clinical trials, the review covers potentially promising anticancer agents, which are grouped based on their structural type and include terpenes, steroids, peptides, polyketides and nitrogen‐containing compounds. The “promise” of a mollusk‐derived natural product as an anticancer agent is evaluated on the basis of its ability to target biological characteristics of cancer cells responsible for poor treatment outcomes. These characteristics include high antiproliferative potency against cancer cells in vitro, preferential inhibition of the proliferation of cancer cells over normal ones, mechanism of action via nonapoptotic signaling pathways, circumvention of multidrug resistance phenotype, and high activity in vivo, among others. The review also includes sections on the targeted delivery of mollusk‐derived anticancer agents and solutions to their procurement in quantity.

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“…Both laulimalide and Peloruside A synergistically enhanced MT assembly induced by stabilizing agents, including discodermolide ( 9 ), dictyostatin, paclitaxel, Epothilones A and B, eleutherobin, and cyclostreptin . Furthermore, laulimalide and Peloruside A stabilize the M loop at the taxoid binding site, which contributes to crosstalk and explains the observed synergism between these agents and taxane site ligands …”

Section: Introductionmentioning

confidence: 99%

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Arnst

Banerjee

Chen

et al. 2019

Medicinal Research Reviews

111

107

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Microtubule (MT)‐targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT‐targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.

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Structural Basis of Microtubule Stabilization by Laulimalide and Peloruside A

Cited by 124 publications

References 20 publications

Design, Synthesis, and Preclinical Evaluation of 4-Substituted-5-methyl-furo[2,3-d]pyrimidines as Microtubule Targeting Agents That Are Effective against Multidrug Resistant Cancer Cells

Design, Synthesis, and Preclinical Evaluation of 4-Substituted-5-methyl-furo[2,3-d]pyrimidines as Microtubule Targeting Agents That Are Effective against Multidrug Resistant Cancer Cells

Marine Mollusk‐Derived Agents with Antiproliferative Activity as Promising Anticancer Agents to Overcome Chemotherapy Resistance

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

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