A Novel Phthalimide Derivative, TC11, Has Preclinical Effects on High-Risk Myeloma Cells and Osteoclasts

作者：Matsushita Maiko; Ozaki Yoshie; Hasegawa Yuka; Terada Fukiko; Tabata Noriko; Shiheido Hirokazu; Yanagawa Hiroshi; Oikawa Tsukasa; Matsuo Koichi; Du Wenlin; Yamada Taketo; Hozumi Masashi; Ichikawa Daiju; Hattori Yutaka^*

来源：PLos One, 2015, 10(1): e0116135.

DOI：10.1371/journal.pone.0116135

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 C-max was 2.1 mu M 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 alpha-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.

• 出版日期2015-1-24