title: An anilinoquinazoline derivative inhibits tumor growth through interaction with hCAP-G2, a subunit of condensin II.
abstract: We screened 46 novel anilinoquinazoline derivatives for activity to inhibit proliferation of a panel of human cancer cell lines. Among them, Q15 showed potent in vitro growth-inhibitory activity towards cancer cell lines derived from colorectal cancer, lung cancer and multiple myeloma. It also showed antitumor activity towards multiple myeloma KMS34 tumor xenografts in lcr/scid mice in vivo. Unlike the known anilinoquinazoline derivative gefitinib, Q15 did not inhibit cytokine-mediated intracellular tyrosine phosphorylation. Using our mRNA display technology, we identified hCAP-G2, a subunit of condensin II complex, which is regarded as a key player in mitotic chromosome condensation, as a Q15 binding partner. Immunofluorescence study indicated that Q15 compromises normal segregation of chromosomes, and therefore might induce apoptosis. Thus, our results indicate that hCAP-G2 is a novel therapeutic target for development of drugs active against currently intractable neoplasms.
authors.affiliation: Department of Biosciences and Informatics, Keio University, Kohoku-ku, Yokohama, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Shiheido
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Naito
authors.forename: Hironobu
authors.initials: H
authors.lastname: Kimura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Genma
authors.forename: Hideaki
authors.initials: H
authors.lastname: Takashima
authors.forename: Mayuko
authors.initials: M
authors.lastname: Tokunaga
authors.forename: Takao
authors.initials: T
authors.lastname: Ono
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hirano
authors.forename: Wenlin
authors.initials: W
authors.lastname: Du
authors.forename: Taketo
authors.initials: T
authors.lastname: Yamada
authors.forename: Nobuhide
authors.initials: N
authors.lastname: Doi
authors.forename: Shiro
authors.initials: S
authors.lastname: Iijima
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hattori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yanagawa
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020090:Chromosome Segregation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009101:Multiple Myeloma / Q000473:pathology; D046912:Multiprotein Complexes / Q000737:chemistry*; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism*; D012306:Risk; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D021122:Protein Subunits; D013844:Thiazoles; C108312:condensin complexes; C027348:2-anilino-5-thiazolinone; D000251:Adenosine Triphosphatases