title: Synthesis and biological activity of analogues of the antimicrotubule agent N,beta,beta-trimethyl-L-phenylalanyl-N(1)-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]- N(1),3-dimethyl-L-valinamide (HTI-286).
abstract: Hemiasterlin, a tripeptide isolated from marine sponges, induces microtubule depolymerization and mitotic arrest in cells. HTI-286, an analogue from an initial study of the hemiasterlins, is presently in clinical trials. In addition to its potent antitumor effects, 2 has the advantage of circumventing the P-glycoprotein-mediated resistance that hampers the efficacy of other antimicrotubule agents such as paclitaxel and vincristine in animal models. This paper describes an in-depth study of the structure--activity relationships of analogues of 2, their effects on microtubule polymerization, and their in vitro and in vivo anticancer activity. Regions of the molecule necessary for potent activity are identified. Groups tolerant of modification, leading to novel analogues, are reported. Potent analogues identified through in vivo studies in tumor xenograft models include one superior analogue, HTI-042.
authors.affiliation: Chemical and Screening Sciences, and Oncology Research,Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA. zaska@wyeth.com
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
authors.forename: Gary
authors.initials: G
authors.lastname: Birnberg
authors.forename: Katherine
authors.initials: K
authors.lastname: Cheung
authors.forename: Joshua
authors.initials: J
authors.lastname: Kaplan
authors.forename: Chuan
authors.initials: C
authors.lastname: Niu
authors.forename: Emily
authors.initials: E
authors.lastname: Norton
authors.forename: Ronald
authors.initials: R
authors.lastname: Suayan
authors.forename: Ayako
authors.initials: A
authors.lastname: Yamashita
authors.forename: Derek
authors.initials: D
authors.lastname: Cole
authors.forename: Zhilian
authors.initials: Z
authors.lastname: Tang
authors.forename: Girija
authors.initials: G
authors.lastname: Krishnamurthy
authors.forename: Robert
authors.initials: R
authors.lastname: Williamson
authors.forename: Gulnaz
authors.initials: G
authors.lastname: Khafizova
authors.forename: Sylvia
authors.initials: S
authors.lastname: Musto
authors.forename: Richard
authors.initials: R
authors.lastname: Hernandez
authors.forename: Tami
authors.initials: T
authors.lastname: Annable
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Yang
authors.forename: Carolyn
authors.initials: C
authors.lastname: Discafani
authors.forename: Carl
authors.initials: C
authors.lastname: Beyer
authors.forename: Lee M
authors.initials: LM
authors.lastname: Greenberger
authors.forename: Frank
authors.initials: F
authors.lastname: Loganzo
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003500:Cyclization; D004952:Esters / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008744:Methylamines / Q000138:chemical synthesis / Q000737:chemistry; D051379:Mice; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D015394:Molecular Structure; D009369:Neoplasms / Q000473:pathology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D019289:Pyruvic Acid / Q000737:chemistry; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
chemical_list: D000588:Amines; D004952:Esters; C473896:HTI-286; D008744:Methylamines; D009842:Oligopeptides; D010455:Peptides; D014404:Tubulin; D019289:Pyruvic Acid; C027451:methylamine