title: In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B.
abstract: Halichondrin B is a highly potent anticancer agent originally found in marine sponges. Although scarcity of the natural product has hampered efforts to develop halichondrin B as a new anticancer drug, the existence of a complete synthetic route has allowed synthesis of structurally simpler analogues that retain the remarkable potency of the parent compound. In this study, we show that two macrocyclic ketone analogues of halichondrir B, ER-076349 and ER-086526, have sub-nM growth inhibitory activities in vitro against numerous human cancer cell lines as well as marked in vivo activities at 0.1-1 mg/kg against four human xenografts: MDA-MB-435 breast cancer, COLO 205 colon cancer, LOX melanoma, and NIH: OVCAR-3 ovarian cancer. ER-076349 and ER-086526 induce G2-M cell cycle arrest and disruption of mitotic spindles, consistent with the tubulin-based antimitotic mechanism of halichondrin B. This is supported further by direct binding of the biotinylated analogue ER-040798 to tubulin and inhibition of tubulin polymerization in vitro by ER-076349 and ER-086526. Retention of the extraordinary in vitro and in vivo activity off halichondrin B in structurally simplified, fully synthetic analogues establishes the feasibility of developing halichondrin B-based agents as highly effective, novel anticancer drugs.
authors.affiliation: Department of Anticancer Research Eisai Research Institute. Andover, Massachusetts 01810, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Towle
authors.forename: K A
authors.initials: KA
authors.lastname: Salvato
authors.forename: J
authors.initials: J
authors.lastname: Budrow
authors.forename: B F
authors.initials: BF
authors.lastname: Wels
authors.forename: G
authors.initials: G
authors.lastname: Kuznetsov
authors.forename: K K
authors.initials: KK
authors.lastname: Aalfs
authors.forename: S
authors.initials: S
authors.lastname: Welsh
authors.forename: W
authors.initials: W
authors.lastname: Zheng
authors.forename: B M
authors.initials: BM
authors.lastname: Seletsky
authors.forename: M H
authors.initials: MH
authors.lastname: Palme
authors.forename: G J
authors.initials: GJ
authors.lastname: Habgood
authors.forename: L A
authors.initials: LA
authors.lastname: Singer
authors.forename: L V
authors.initials: LV
authors.lastname: Dipietro
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: J J
authors.initials: JJ
authors.lastname: Chen
authors.forename: D A
authors.initials: DA
authors.lastname: Quincy
authors.forename: A
authors.initials: A
authors.lastname: Davis
authors.forename: K
authors.initials: K
authors.lastname: Yoshimatsu
authors.forename: Y
authors.initials: Y
authors.lastname: Kishi
authors.forename: M J
authors.initials: MJ
authors.lastname: Yu
authors.forename: B A
authors.initials: BA
authors.lastname: Littlefield
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D019921:Biotinylation; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004988:Ethers, Cyclic / Q000494:pharmacology*; D005260:Female; D005663:Furans; D016195:G2 Phase / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000494:pharmacology*; D018942:Macrolides; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D001710:Biotin; D004988:Ethers, Cyclic; D005663:Furans; D006131:Growth Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D007659:Ketones; D018942:Macrolides; D014404:Tubulin; D050257:Tubulin Modulators; C421616:ER 076349; C070519:halichondrin B; D000095662:Polyether Polyketides; C490954:eribulin