title: HTI-286, a synthetic analogue of the tripeptide hemiasterlin, is a potent antimicrotubule agent that circumvents P-glycoprotein-mediated resistance in vitro and in vivo.
abstract: Hemiasterlin is a natural product derived from marine sponges that, like other structurally diverse peptide-like molecules, binds to the Vinca-peptide site in tubulin, disrupts normal microtubule dynamics, and, at stoichiometric amounts, depolymerizes microtubules. Total synthesis of hemiasterlin and its analogues has been accomplished, and optimal pharmacological features of the series have been explored. The biological profile of one analogue, HTI-286, was studied here. HTI-286 inhibited the polymerization of purified tubulin, disrupted microtubule organization in cells, and induced mitotic arrest, as well as apoptosis. HTI-286 was a potent inhibitor of proliferation (mean IC(50) = 2.5 +/- 2.1 nM in 18 human tumor cell lines) and had substantially less interaction with multidrug resistance protein (P-glycoprotein) than currently used antimicrotubule agents, including paclitaxel, docetaxel, vinorelbine, or vinblastine. Resistance to HTI-286 was not detected in cells overexpressing the drug transporters MRP1 or MXR. In athymic mice implanted with human tumor xenografts, HTI-286 administered i.v. in saline inhibited the growth of numerous human tumors derived from carcinoma of the skin, breast, prostate, brain, and colon. Marked tumor regression was observed when used on established tumors that were >1 gram in size. Moreover, HTI-286 inhibited the growth of human tumor xenografts (e.g., HCT-15, DLD-1, MX-1W, and KB-8-5) where paclitaxel and vincristine were ineffective because of inherent or acquired resistance associated with P-glycoprotein. Efficacy was also achieved with p.o. administration of HTI-286. These data suggest that HTI-286 has excellent preclinical properties that may translate into superior clinical activity, as well as provide a useful synthetic reagent to probe the drug contact sites of peptide-like molecules that interact with tubulin.
authors.affiliation: Oncology Research, Wyeth Research, Pearl River, New York 10965, USA. loganzf@wyeth.com
authors.forename: Frank
authors.initials: F
authors.lastname: Loganzo
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Discafani
authors.forename: Tami
authors.initials: T
authors.lastname: Annable
authors.forename: Carl
authors.initials: C
authors.lastname: Beyer
authors.forename: Sylvia
authors.initials: S
authors.lastname: Musto
authors.forename: Malathi
authors.initials: M
authors.lastname: Hari
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Tan
authors.forename: Carolyn
authors.initials: C
authors.lastname: Hardy
authors.forename: Richard
authors.initials: R
authors.lastname: Hernandez
authors.forename: Michelle
authors.initials: M
authors.lastname: Baxter
authors.forename: Thiruvikraman
authors.initials: T
authors.lastname: Singanallore
authors.forename: Gulnaz
authors.initials: G
authors.lastname: Khafizova
authors.forename: Marianne S
authors.initials: MS
authors.lastname: Poruchynsky
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
authors.forename: James A
authors.initials: JA
authors.lastname: Nieman
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.forename: Lee M
authors.initials: LM
authors.lastname: Greenberger
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007624:KB Cells; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; C473896:HTI-286; D009842:Oligopeptides; D014404:Tubulin; C467070:hemiasterlin