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

• 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
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0044889

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.