title: A novel phthalimide derivative, TC11, has preclinical effects on high-risk myeloma cells and osteoclasts.
abstract: Despite the recent advances in the treatment of multiple myeloma (MM), MM patients with high-risk cytogenetic changes such as t(4;14) translocation or deletion of chromosome 17 still have extremely poor prognoses. With the goal of helping these high-risk MM patients, we previously developed a novel phthalimide derivative, TC11. Here we report the further characterization of TC11 including anti-myeloma effects in vitro and in vivo, a pharmacokinetic study in mice, and anti-osteoclastogenic activity. Intraperitoneal injections of TC11 significantly delayed the growth of subcutaneous tumors in human myeloma-bearing SCID mice. Immunohistochemical analyses showed that TC11 induced apoptosis of MM cells in vivo. In the pharmacokinetic analyses, the Cmax was 2.1 μM at 1 h after the injection of TC11, with 1.2 h as the half-life. TC11 significantly inhibited the differentiation and function of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts in mouse osteoclast cultures using M-CSF and RANKL. We also revealed that TC11 induced the apoptosis of myeloma cells accompanied by α-tubulin fragmentation. In addition, TC11 and lenalidomide, another phthalimide derivative, directly bound to nucleophosmin 1 (NPM1), whose role in MM is unknown. Thus, through multiple molecular interactions, TC11 is a potentially effective drug for high-risk MM patients with bone lesions. The present results suggest the possibility of the further development of novel thalidomide derivatives by drug designing.
authors.affiliation: Clinical Physiology and Therapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Clinical Physiology and Therapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Ozaki
authors.affiliation: Clinical Physiology and Therapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Clinical Physiology and Therapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Fukiko
authors.initials: F
authors.lastname: Terada
authors.affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Tabata
authors.affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Shiheido
authors.affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yanagawa
authors.affiliation: Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Oikawa
authors.affiliation: Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Du
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Taketo
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Clinical Physiology and Therapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Hozumi
authors.affiliation: Clinical Physiology and Therapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Daiju
authors.initials: D
authors.lastname: Ichikawa
authors.affiliation: Clinical Physiology and Therapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hattori
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D064593:Heterografts / Q000187:drug effects; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000737:chemistry; D000090243:Nucleophosmin; D010010:Osteoclasts / Q000187:drug effects; D010797:Phthalimides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013792:Thalidomide / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: C579116:2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3-dione; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D010797:Phthalimides; D000090243:Nucleophosmin; D013792:Thalidomide; D000077269:Lenalidomide