Halichondrin B

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David R Gandara - One of the best experts on this subject based on the ideXlab platform.

Ernest Hamel - One of the best experts on this subject based on the ideXlab platform.

  • Interactions of <B>HalichondrinB> B and EriBulin with TuBulin
    Journal of chemical information and modeling, 2011
    Co-Authors: Ruoli Bai, George R Pettit, Tam Luong Nguyen, James C. Burnett, Onur Atasoylu, Murray H. G. Munro, Amos B. Smith, Rick Gussio, Ernest Hamel
    Abstract:

    Compounds that modulate microtuBule dynamics include highly effective anticancer drugs, leading to continuing efforts to identify new agents and improve the activity of estaBlished ones. Here, we demonstrate that [3H]-laBeled <B>HalichondrinB> B (HB), a complex, sponge-derived natural product, is Bound to and dissociated from tuBulin rapidly at one Binding site per αβ-heterodimer, with an apparent Kd of 0.31 μM. We found no HB-induced aggregation of tuBulin By high-performance liquid chromatography, even following column equiliBration with HB. Binding of [3H]HB was competitively inhiBited By a newly approved clinical agent, the truncated HB analogue eriBulin (apparent Ki, 0.80 μM) and noncompetitively By dolastatin 10 and vincristine (apparent Ki’s, 0.35 and 5.4 μM, respectively). Our earlier studies demonstrated that HB inhiBits nucleotide exchange on β-tuBulin, and this, together with the results presented here, indicated the HB site is located on β-tuBulin. Using molecular dynamics simulations, we determine...

  • ABstract #5570: Interaction of [³H]<B>HalichondrinB> B with tuBulin
    Cancer Research, 2009
    Co-Authors: Ruoli Bai, Ernest Hamel
    Abstract:

    <B>HalichondrinB> B is a sponge-derived, complex natural product that Binds in the vinca domain of tuBulin and inhiBits tuBulin assemBly. It noncompetitively inhiBits the Binding of Both radiolaBeled vinBlastine and radiolaBeled dolastatin 10 to tuBulin. Although <B>HalichondrinB> B has excellent antitumor activity in vivo, scarcity of the natural product led to development of a truncated analog, NSC 707389 (eriBulin), that is presently in late clinical trials. To gain greater insight into the interactions of <B>HalichondrinB> B with tuBulin, we commissioned the preparation of tritiated <B>HalichondrinB> B and have Been studying its interactions with tuBulin. Binding is nearly instantaneous and not covalent. We examined inhiBitory effects of 16 vinca domain compounds and found that only NSC 707389 and the antimitotic peptides dolastatin 10 and, to a lesser extent, hemiasterlin were strong inhiBitors of <B>HalichondrinB> B Binding to tuBulin. Preliminary studies indicate that NSC 707389 is a competitive inhiBitor of <B>HalichondrinB> B Binding, while dolastatin 10 is a noncompetitive inhiBitor. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. ABstract nr 5570.

  • aBstract 5570 interaction of h <B>HalichondrinB> B with tuBulin
    Cancer Research, 2009
    Co-Authors: Ruoli Bai, Ernest Hamel
    Abstract:

    <B>HalichondrinB> B is a sponge-derived, complex natural product that Binds in the vinca domain of tuBulin and inhiBits tuBulin assemBly. It noncompetitively inhiBits the Binding of Both radiolaBeled vinBlastine and radiolaBeled dolastatin 10 to tuBulin. Although <B>HalichondrinB> B has excellent antitumor activity in vivo, scarcity of the natural product led to development of a truncated analog, NSC 707389 (eriBulin), that is presently in late clinical trials. To gain greater insight into the interactions of <B>HalichondrinB> B with tuBulin, we commissioned the preparation of tritiated <B>HalichondrinB> B and have Been studying its interactions with tuBulin. Binding is nearly instantaneous and not covalent. We examined inhiBitory effects of 16 vinca domain compounds and found that only NSC 707389 and the antimitotic peptides dolastatin 10 and, to a lesser extent, hemiasterlin were strong inhiBitors of <B>HalichondrinB> B Binding to tuBulin. Preliminary studies indicate that NSC 707389 is a competitive inhiBitor of <B>HalichondrinB> B Binding, while dolastatin 10 is a noncompetitive inhiBitor. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. ABstract nr 5570.

  • Comparison of the Activities of the Truncated <B>HalichondrinB> B Analog NSC 707389 (E7389) with Those of the Parent Compound and a Proposed Binding Site on TuBulin
    Molecular pharmacology, 2006
    Co-Authors: Donnette A. Dabydeen, George R Pettit, Ruoli Bai, James C. Burnett, Murray H. G. Munro, Rick Gussio, Pascal Verdier-pinard, Sarah J. H. Hickford, John W. Blunt, Ernest Hamel
    Abstract:

    The complex marine natural product <B>HalichondrinB> B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has Been selected for clinical trials in human patients. NSC 707389 was invariaBly more potent than <B>HalichondrinB> B in its interactions with tuBulin. Both compounds inhiBited tuBulin assemBly, inhiBited nucleotide exchange on Beta-tuBulin, and were noncompetitive inhiBitors of the Binding of radiolaBeled vinBlastine and dolastatin 10 to tuBulin. Neither compound seemed to induce an aBerrant tuBulin assemBly reaction, as occurs with vinBlastine (tight spirals) or dolastatin 10 (aggregated rings and spirals). We modeled the two compounds into a shared Binding site on tuBulin consistent with their Biochemical properties. Of the two tuBulin structures availaBle, we selected for modeling the complex of a stathmin fragment with two tuBulin heterodimers with two Bound colchicinoid molecules and a single Bound vinBlastine Between the two heterodimers (Nature (Lond) 435:519-522, 2005). <B>HalichondrinB> B and NSC 707389 fit snugly Between the two heterodimers adjacent to the exchangeaBle site nucleotide. Fitting the compounds into this site, which was also close to the vinBlastine site, resulted in enough movement of amino acid residues at the vinBlastine site to cause the latter compound to Bind less well to tuBulin. The model suggests that <B>HalichondrinB> B and NSC 707389 most likely form highly unstaBle, small aBerrant tuBulin polymers rather than the massive staBle structures oBserved with vinca alkaloids and antimitotic peptides.

  • Isolation and Structure of Halistatin 1 from the Eastern Indian Ocean Marine Sponge Phakellia carteri
    The Journal of Organic Chemistry, 1993
    Co-Authors: George R Pettit, Ernest Hamel, Rui Tan, Feng Gao, Michael D. Williams, Dennis L. Doubek, Michael R. Boyd, Jean M. Schmidt, Jean Chapuis, Ruoli Bai
    Abstract:

    A highly potent new polyether macrolide antimitotic agent designated halistatin 1 (5) was isolated (8.8×10 -7 % yield) from Phakellia carteri. The marine sponge was located in coastal areas of the RepuBlic of the Comoros, and it was also found to contain <B>HalichondrinB> B (3) and homo<B>HalichondrinB> B (4). Structure elucidation of halistatin 1 (5) was achieved primarily By employing extensive high-field (400 and 500-MHz) 2D NMR techniques. Halistatin 1, like <B>HalichondrinB> B and homo<B>HalichondrinB> B, caused the accumulation of cells arrested in mitosis, inhiBited tuBulin polymerization, and inhiBited the Binding of radiolaBeled vinBlastine and GTP to tuBulin

Osamu Yonemitsu - One of the best experts on this subject based on the ideXlab platform.

Marianna Koczywas - One of the best experts on this subject based on the ideXlab platform.

  • Phase I study of the <B>HalichondrinB> B analogue eriBulin mesylate in comBination with cisplatin in advanced solid tumors
    British Journal of Cancer, 2014
    Co-Authors: Marianna Koczywas, Timothy W. Synold, Anthony B. El-khoueiry, P H Frankel, H-j Lenz, J E Mortimer, D R Gandara, M C Cristea, V M Chung, D Lim
    Abstract:

    Background: EriBulin mesylate is a synthetic macrocyclic ketone analogue of <B>HalichondrinB> B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in comBination with cisplatin (CP) in patients with advanced solid tumours. Methods: Thirty-six patients with advanced solid tumours received eriBulin mesylate 0.7–1.4 mg m^−2 and CP 60–75 mg m^−2. EriBulin mesylate was administered on days 1, 8, and 15 in comBination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eriBulin mesylate 1.4 mg m^−2, CP 60 mg m^−2) when it was not feasiBle to administer eriBulin mesylate on day 15 Because of neutropenia; the treatment schedule was changed to eriBulin mesylate on days 1 and 8 and CP on day 1 every 21 days. Results: On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 feBrile neutropenia (1.0 mg m^−2, 60 mg m^−2); G 3 anorexia/fatigue/hypokalemia (1.2 mg m^−2, 60 mg m^−2); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m^−2, 60 mg m^−2). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m^−2, 60 mg m^−2); G 4 mucositis (1.4 mg m^−2, 60 mg m^−2); and G 3 hypokalemia (1.2 mg m^−2, 75 mg m^−2). The MTD and recommended phase II dose was determined as eriBulin mesylate 1.2 mg m^−2 (days 1, 8) and CP 75 mg m^−2 (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and Breast cancers) and two had PR (oesophageal and Bladder cancers). Conclusions: On the 21-day cycle, eriBulin mesylate 1.2 mg m^−2, administered on days 1 and 8, in comBination with CP 75 mg m^−2, administered on day 1 is well tolerated and showed preliminary anticancer activity.

  • Phase I study of the <B>HalichondrinB> B analogue eriBulin mesylate in comBination with cisplatin in advanced solid tumors
    British journal of cancer, 2014
    Co-Authors: Marianna Koczywas, Heinzjosef Lenz, Joanne E Mortimer, Paul Frankel, David R Gandara, Mihaela C Cristea, Vincent Chung, Timothy W. Synold, Anthony B. El-khoueiry, Dean Lim
    Abstract:

    Phase I study of the <B>HalichondrinB> B analogue eriBulin mesylate in comBination with cisplatin in advanced solid tumors

  • phi 55 nci 7427 a phase i study of <B>HalichondrinB> B analog e7389 in comBination with cisplatin cddp in advanced solid tumors a ccc nci ctep sponsored trial grant u01 ca 062505
    Journal of Clinical Oncology, 2013
    Co-Authors: Marianna Koczywas, Heinzjosef Lenz, Joanne E Mortimer, Anthony B Elkhoueiry, Paul Frankel, David R Gandara, Mihaela C Cristea, Vincent Chung, Dean Lim, Karen L Reckamp
    Abstract:

    2564 Background: E7389 is a structurally simplified synthetic macrocyclic ketone analog of the marine sponge natural product <B>HalichondrinB> B, which inhiBits microtuBule dynamics via a novel mechanis...

  • PHI-55: (NCI#7427): A phase I study of <B>HalichondrinB> B analog (E7389) in comBination with cisplatin (CDDP) in advanced solid tumors: A CCC, NCI/CTEP-sponsored trial (grant U01 CA 062505).
    Journal of Clinical Oncology, 2013
    Co-Authors: Marianna Koczywas, Heinzjosef Lenz, Joanne E Mortimer, Paul Frankel, David R Gandara, Mihaela C Cristea, Vincent Chung, Dean Lim, Anthony B. El-khoueiry, Karen L Reckamp
    Abstract:

    2564 Background: E7389 is a structurally simplified synthetic macrocyclic ketone analog of the marine sponge natural product <B>HalichondrinB> B, which inhiBits microtuBule dynamics via a novel mechanis...

  • A Phase II Study of <B>HalichondrinB> B Analog EriBulin Mesylate (E7389) in Patients with Advanced Non-small Cell Lung Cancer Previously Treated with a Taxane: A California Cancer Consortium Trial
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2012
    Co-Authors: Barbara J Gitlitz, Marianna Koczywas, Angela M Davies, Chandra P Belani, Athanassios Argiris, S G Groshen, Denice D. Tsao-wei, Suresh S. Ramalingam, Everett E. Vokes, Martin J. Edelman
    Abstract:

    Introduction EriBulin mesylate (E7389) is an analog of <B>HalichondrinB> B with a unique mechanism of microtuBule Binding. The activity and toxicity of eriBulin were assessed in patients with advanced non-small cell lung cancer (NSCLC) previously treated with a taxane. Methods An open-laBel phase II study included patients with NSCLC previously treated with platinum and taxane-Based therapy, with up to two prior cytotoxic regimens, given for metastatic disease or as adjuvant therapy. Patients were stratified By taxane-sensitivity: taxane-sensitive (TS, progression >90 days after taxane) or taxane-resistant (TR, progression ⩽90 days after taxane). Patients received an intravenous infusion of eriBulin at 1.4 mg/m 2 on days 1 and 8 every 21 days. The primary end point was oBjective response rate and secondary end points included progression-free survival and overall survival. Results Sixty-six patients were accrued. The oBjective response rate was 5% with a median duration of response of 7.8 months. In the TS arm, 3 of 45 patients (7%) achieved a partial response and another 11 of 45 (24%) achieved staBle disease for at least 3 months, whereas in the TR arm, no patients achieved a partial response and 4 of 21 (19%) achieved staBle disease for at least 3 months. Median progression-free survival was 2.9 months in the TS suBgroup and 1.2 months in the TR suBgroup. The median overall survival was 12.6 months in the TS suBgroup and 8.9 months in the TR suBgroup. Toxicities were primarily hematologic; only two patients developed grade 3 neuropathy. Conclusions EriBulin mesylate is well tolerated and demonstrates activity in pretreated, TS NSCLC.

Bruce A. Littlefield - One of the best experts on this subject based on the ideXlab platform.

  • Antiproliferative effects of <B>HalichondrinB> B analog eriBulin mesylate (E7389) against paclitaxel-resistant human cancer cells in vitro
    Molecular Cancer Therapeutics, 2007
    Co-Authors: Galina Kuznetsov, Karen Tendyke, Bruce A. Littlefield
    Abstract:

    C58 EriBulin (E7389, ER-086526, NSC-707389), a structurally-simplified synthetic analog of the Biologically active macrocyclic portion of the marine natural product <B>HalichondrinB> B, is currently undergoing Phase 3 clinical trials for metastatic Breast cancer. Preclinical studies have shown that eriBulin exerts potent anticancer activities in vitro and in vivo By inhiBiting microtuBule dynamics via a mechanism distinct from other tuBulin-targeted agents. EriBulin inhiBits proliferation of a wide spectrum of human cancer cell types at suB-nanomolar concentrations and shows impressive anticancer activity against a Broad range of human cancer xenograft models in mice, including complete tumor regressions. To further evaluate eriBulin as an anticancer agent, its activity against drug-resistant human cancer cells was studied. Cancer cells can acquire resistance to chemotherapy agents By several different mechanisms. One mechanism with particular relevance to some tuBulin-targeted drugs involves mutations in β-tuBulin that result in decreased responsiveness to tuBulin-targeted agents such as the taxanes. In this study, antiproliferative effects of eriBulin were evaluated in an in vitro cell-Based model of resistance Based on mutated β-tuBulin. Three ovarian cancer cell lines, A2780/1A9, 1A9PTX10 and 1A9PTX22, were oBtained from the laBoratory of Dr. Tito Fojo, US National Cancer Institute. The two paclitaxel resistant suBlines of A2780/1A9, 1A9PTX10 and 1A9PTX22, were originally isolated as individual clones in a single step selection following exposure of A2780/1A9 cells to paclitaxel. Both suBlines harBor different mutations in the M40 β-tuBulin isotype and have Been shown to have significant resistance to paclitaxel. To verify that paclitaxel resistance of 1A9PTX10 and 1A9PTX22 cells is not Based on expression of the multidrug resistance efflux pump P-glycoprotein (PgP), cells were stained with fluorescently-laBeled anti-PgP antiBody and analyzed By flow cytometry. Neither of the 2 resistant lines, 1A9PTX10 or 1A9PTX22, nor parental A2780/1A9 cells, expressed detectaBle PgP, indicating that paclitaxel resistance seen in 1A9PTX10 and 1A9PTX22 cells is not PgP-mediated. Antiproliferative effects of eriBulin, paclitaxel and vinBlastine were then measured in A2780/1A9, 1A9PTX10 and 1A9PTX22 cells. Consistent with literature reports, 1A9PTX10 and 1A9PTX22 cells showed 15- to 19-fold resistance to paclitaxel. In contrast, 1A9PTX10 and 1A9PTX22 cells showed almost identical sensitivities to eriBulin and vinBlastine compared with parental A2780/1A9 cells (IC 50 ratios ~1.3). These results indicate that eriBulin and vinBlastine retain essentially full in vitro potency in cells harBoring β-tuBulin mutations that lead to suBstantial resistance to paclitaxel.

  • induction of morphological and Biochemical apoptosis following prolonged mitotic Blockage By <B>HalichondrinB> B macrocyclic ketone analog e7389
    Cancer Research, 2004
    Co-Authors: Galina Kuznetsov, Murray J Towle, Yoshito Kishi, Hongsheng Cheng, Takanori Kawamura, Karen Tendyke, Melvin J Yu, Bruce A. Littlefield
    Abstract:

    E7389, a macrocyclic ketone analog of the marine natural product <B>HalichondrinB> B, currently is undergoing clinical trials for cancer. This fully synthetic agent exerts its highly potent in vitro and in vivo anticancer effects via tuBulin-Based antimitotic mechanisms, which are similar or identical to those of parental <B>HalichondrinB> B. In an attempt to understand the impressive potency of E7389 in animal models of human cancer, its aBility to induce apoptosis following prolonged mitotic Blockage was evaluated. Treatment of U937 human histiocytic lymphoma cells with E7389 led to time-dependent collection of cells in the G 2 -M phase of the cell cycle, Beginning as early as 2 h and Becoming maximal By 12 h. Increased numBers of hypodiploid events were seen Beginning at 12 h, suggesting initiation of apoptosis after prolonged E7389-induced mitotic Blockage. The identity of hypodiploid events as apoptotic cells under these conditions was confirmed By two additional morphologic criteria: green to orange/yellow shifts on acridine orange/ethidium Bromide staining, and cell surface annexin V Binding as assessed By flow cytometry. Several Biochemical correlates of apoptosis also were seen following E7389 treatment, including phosphorylation of the antiapoptotic protein Bcl-2, cytochrome c release from mitochondria, proteolytic activation of caspase-3 and -9, and cleavage of the caspase-3 suBstrate poly(ADP-riBose) polymerase (PARP). In LNCaP human prostate cancer cells, treatment with E7389 also led to generation of hypodiploid cells, activation of caspase-3 and -9, and appearance of cleaved PARP, indicating that E7389 can activate cellular apoptosis pathways under anchorage-independent and -dependent cell culture conditions. These results show that prolonged mitotic Blockage By E7389 can lead to apoptotic cell death of human cancer cells in vitro and can provide a mechanistic Basis for the significant in vivo anticancer efficacy of E7389.

  • E7389 and ER-076349, synthetic <B>HalichondrinB> B analogs, suppress centromere dynamics in concert with mitotic Block
    Cancer Research, 2004
    Co-Authors: Tatiana Okouneva, Bruce A. Littlefield, Leslie Wilson, Mary Ann Jordan
    Abstract:

    5436 E7389 and ER-076349 are synthetic macrocyclic ketone analogs of <B>HalichondrinB> B with potent antiproliferative activities; E7389 is in Phase I clinical trials. The compounds Bind to tuBulin, inhiBit polymerization of tuBulin into microtuBules at high (micromolar) concentrations, induce G2/M cell cycle arrest, inhiBit tumor cell proliferation at picomolar concentrations, and inhiBit tumor growth (Towle et al., Cancer Res 61: 1013-1021, 2001). Recent work indicates that E7389 appears to work in cells By a novel mechanism, By aggregating tuBulin and thus reducing the rates and lengths of microtuBule growth events in cells (M.A. Jordan, K. Kamath, H. Miller, C. Davis, B.A. Littlefield, and L. Wilson, unpuBlished data). We asked whether this suppression of microtuBule dynamics leads to mitotic Block in living human osteosarcoma cells (U2Os). We used a fluorescently-laBeled centromere-Binding protein (GFP-CENP-B) to quantitate the effects of E7389 and ER-076349 on the dynamic Behavior of spindle microtuBules By high-resolution time-lapse confocal microscopy in the cells. Chromosomes oscillate during prometaphase as they congress to the metaphase plate, and sister chromatids are rhythmically stretched apart and relaxed together By the attached dynamic microtuBules. Spindle microtuBule (+)-ends attached to chromosomes are marked By fluorescent centromeres. Half-maximal mitotic Block was induced By 30 nM E7389 and By 2 nM ER-076349, and complete Block was induced By 1 mM and By 100 nM, respectively. We found that E7389 and ER-076349 altered the centromere stretching /relaxation movements in a concentration-dependent manner, in concert with mitotic Block. For example, in the aBsence of drug, the centromeres spent 68% of the time in movements of stretching and relaxation whereas this percentage was significantly reduced to 53% at 30 nM E7389 and to 59% at 2 nM ER-076349. The time centromeres were paused increased from 31% in untreated cells to 46% and 40% in cells with 30 nM E7389 and 2 nM ER-076349, respectively. Interestingly, the rates of stretching were increased By 27% with 30 nM E7389 and By 13% with 2 nM ER-076349. These results suggest that there are significant differences Between the mechanisms of E7389 and ER-076349 as compared with those of paclitaxel, vincristine, and vinBlastine. The results also support the hypothesis that alterations of microtuBule dynamics play a role in the antimitotic and antitumor activity of E7389 and ER-076349. Supported By a grant from Eisai Research Institute and NIH CA 57291.

  • Structure–activity relationships of <B>HalichondrinB> B analogues: modifications at C.30–C.38
    Bioorganic & medicinal chemistry letters, 2000
    Co-Authors: Yuan Wang, Gregory J. Habgood, William J. Christ, Yoshito Kishi, Bruce A. Littlefield
    Abstract:

    Structurally simplified analogues of <B>HalichondrinB> B were prepared By total synthesis and found to retain potent cell growth inhiBitory activity in vitro.

  • structure activity relationships of <B>HalichondrinB> B analogues modifications at c 30 c 38
    Bioorganic & Medicinal Chemistry Letters, 2000
    Co-Authors: Yuan Wang, Gregory J. Habgood, William J. Christ, Yoshito Kishi, Bruce A. Littlefield
    Abstract:

    Structurally simplified analogues of <B>HalichondrinB> B were prepared By total synthesis and found to retain potent cell growth inhiBitory activity in vitro.

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