An anilinoquinazoline derivative inhibits tumor growth through interaction with hCAP-G2, a subunit of condensin II

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 showe...

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Bibliographic Details
Published in:	PloS one Vol. 7; no. 9; p. e44889
Main Authors:	Shiheido, Hirokazu, Naito, Yuhei, Kimura, Hironobu, Genma, Hiroaki, Takashima, Hideaki, Tokunaga, Mayuko, Ono, Takao, Hirano, Tatsuya, Du, Wenlin, Yamada, Taketo, Doi, Nobuhide, Iijima, Shiro, Hattori, Yutaka, Yanagawa, Hiroshi
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 13-09-2012 Public Library of Science (PLoS)
Subjects:	Acids Adenosine Triphosphatases - chemistry Animals Anticancer properties Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Antitumor activity Apoptosis Apoptosis - drug effects Biology Biotechnology Cancer Cancer prevention Cancer therapies Cancer treatment Cell division Cell Line, Tumor Cell Proliferation - drug effects Chemistry Chromosome Segregation - drug effects Chromosomes Colorectal cancer Colorectal carcinoma Condensin Display devices DNA-Binding Proteins - chemistry Drug development Drug Resistance, Neoplasm - drug effects Gefitinib Growth Growth factors Humans Immunofluorescence Informatics Kinases Laboratories Lung cancer Lung diseases Male Medicine Mice Mitosis - drug effects mRNA Multiple myeloma Multiple Myeloma - pathology Multiprotein Complexes - chemistry Neoplasia Neoplasms Pharmacy Phosphorylation Physiology Protein Binding Protein Subunits - metabolism Proteins Risk RNA Rodents Therapeutic applications Thiazoles - metabolism Thiazoles - pharmacology Tumor cell lines Tumors Tyrosine Xenograft Model Antitumor Assays Xenografts Xenotransplantation Japan
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Summary:	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.
Bibliography:	Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: HS YN HK HT TO TH WD TY SI YH HY. Performed the experiments: HS YN HK HG HT MT TO WD SI. Analyzed the data: HS YN HK HT MT TO TH WD TY ND SI YH HY. Contributed reagents/materials/analysis tools: HT TH TY ND SI YH HY. Wrote the paper: HS YN TO TY ND YH HY.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0044889