Interaction of cryptophycin 1 with tubulin and microtubules

Kerksiek, Kristen M.; Mejillano, Magdalena R.; Schwartz, Robert E.; Georg, Gunda I.; Himes, Richard H.

doi:10.1016/0014-5793(95)01271-0

Cited by 83 publications

(77 citation statements)

References 11 publications

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“…The parent compound, cryptophycin-1, inhibits cell proliferation by blocking cell cycle progression at prometaphase͞metaphase of mitosis at picomolar concentrations by an apparent action on microtubules (21)(22)(23)(24)(25). In vitro, cryptophycin-1 inhibits microtubule polymerization (23,24,26) and strongly suppresses the dynamic instability of microtubules (27).…”

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confidence: 99%

Antiproliferative mechanism of action of cryptophycin-52: Kinetic stabilization of microtubule dynamics by high-affinity binding to microtubule ends

Panda

DeLuca

Williams

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

116

104

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Cryptophycin-52 (LY355703) is a new synthetic member of the cryptophycin family of antimitotic antitumor agents that is currently undergoing clinical evaluation. At high concentrations (>10 times the IC 50 ), cryptophycin-52 blocked HeLa cell proliferation at mitosis by depolymerizing spindle microtubules and disrupting chromosome organization. However, low concentrations of cryptophycin-52 inhibited cell proliferation at mitosis (IC 50 ‫؍‬ 11 pM) without significantly altering spindle microtubule mass or organization. Cryptophycin-52 appears to be the most potent suppressor of microtubule dynamics found thus far. It suppressed the dynamic instability behavior of individual microtubules in vitro (IC 50 ‫؍‬ 20 nM), reducing the rate and extent of shortening and growing without significantly reducing polymer mass or mean microtubule length. Using [ 3 H]cryptophycin-52, we found that the compound bound to microtubule ends in vitro with high affinity (K d , 47 nM, maximum of Ϸ19.5 cryptophycin-52 molecules per microtubule). By analyzing the effects of cryptophycin-52 on dynamics in relation to its binding to microtubules, we determined that Ϸ5-6 molecules of cryptophycin-52 bound to a microtubule were sufficient to decrease dynamicity by 50%. Cryptophycin-52 became concentrated in cells 730-fold, and the resulting intracellular cryptophycin-52 concentration was similar to that required to stabilize microtubule dynamics in vitro. The data suggest that cryptophycin-52 potently perturbs kinetic events at microtubule ends that are required for microtubule function during mitosis and that it acts by forming a reversible cryptophycin-52-tubulin stabilizing cap at microtubule ends.

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confidence: 99%

Antiproliferative mechanism of action of cryptophycin-52: Kinetic stabilization of microtubule dynamics by high-affinity binding to microtubule ends

Panda

DeLuca

Williams

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

116

104

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“…It inhibits tubulin polymerization with an IC 50 value of 1 μM (Kerksiek et al 1995) by binding to the vinca domain (Bai et al 1996;Smith and Zhang 1996), and induces mitotic arrest and apoptosis (Mooberry et al 1997). A similar peptide named arenastatin A has been isolated from a marine sponge (Kobayashi et al 1994a).…”

Section: Fig 11mentioning

confidence: 99%

Developmental Biology of Neoplastic Growth

Macieira‐Coelho¹

2005

Progress in Molecular and Subcellular Biology

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“…The acid (40 mg, 0.10 mmol) and salt 8a (40 mg, 12. tert-Butyl-(2E)-5-[(2S)-4-methyl-2-(1,1,2,2-tetramethyl-0.140 mmol) were placed in a flask and CH 3 CN (1 mL) was I-silapropoxy)pentanoyloxy]-(5S,6/•-6-methylocta-2,7-added. The solution was cooled to 0 0C and DIEA (52 ,L, 0.30 dienoate (12). The aldehyde (80 mng, 0.22 mmol) was dissolved mmol) was added.…”

Section: Reportable Outcomesmentioning

confidence: 99%

Synthesis of Cryptophycin Affinity Labels and Tubulin Labeling

Yang¹,

Georg²

2006

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Public reporting burden for this collection of information is estimated to average I hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of Information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and ABSTRACT (Maximum 200 Words)Cryptophycins are a potent, tumor-selective class of tubulin-binding antimitotic anticancer agents with excellent activity against MDR cancers. For the development of these promising compounds into useful chemotherapeutic agents, detailed information about the binding domain of the cryptophycins is essential. We plan to map the cryptophycin binding site through photoaffinity labeling studies. Toward this goal we have prepared CIO azido analogues of cryptophycin-24 and have evaluated them in a tubulin assembly assay. We have found them to be potential candidates for photoaffinity labeling studies. IntroductionCryptophycins, isolated from blue-green algae (Nostoc sp.), are a new and potent tumor-selective class of tubulin-binding antimitotic agents that show excellent activity against MDR cancer cell lines and were exceptionally active against mammary derived tumors."2 Cryptophycin-1 (1, Fig. 1) is the major cytotoxin in Nostoc sp. 3 ' 4 and displays IC 50 values in the pM range. Of special importance is the reduced susceptibility of the cryptophycins to P-glycoprotein mediated multiple drug resistance in comparison to vinblastine, colchicine, and paclitaxel. A structurally related compound cryptophycin-24, (2, Fig. 1, also named arenastatin A), isolated from the Okinawan marine sponge Dysidea arenaria 5 and later from Nostoc sp. strain GSV 224,6 is also a potent inhibitor of tubulin polymerization. Cryptophycins are one of the best recent lead in the search for anticancer therapies. Formal and total syntheses of the cryptophycins have been published by several groups.7 " Also, wide SAR studies of these molecules have been reported.I" 2 Although relatively little is known about the interactions of cryptophycins with tubulin, it is believed that the cryptophycins may interact in a manner different from those of other tubulin-binding antimitotic agents.12' 4 For the development of these promising compounds into useful chemotherapeutic agents, detailed information about the binding domain of the cryptophycins is essential. Hence, we planned to prepare analogues with affinity labels at the two aromatic rings of the cryptophycin molecule. The information obtained will be used to search for effective bioactive candidates for in vitro and in vivo testing. We have already synthesized and evaluated three C16 side chain benzophenone"' and azido (meta and para)' 6 analogues of cryptophycin-24. Although these...

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Interaction of cryptophycin 1 with tubulin and microtubules

Cited by 83 publications

References 11 publications

Antiproliferative mechanism of action of cryptophycin-52: Kinetic stabilization of microtubule dynamics by high-affinity binding to microtubule ends

Antiproliferative mechanism of action of cryptophycin-52: Kinetic stabilization of microtubule dynamics by high-affinity binding to microtubule ends

Developmental Biology of Neoplastic Growth

Synthesis of Cryptophycin Affinity Labels and Tubulin Labeling

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