A novel phthalimide derivative, TC11, has preclinical effects on high-risk myeloma cells and osteoclasts

PLoS One. 2015 Jan 24;10(1):e0116135. doi: 10.1371/journal.pone.0116135. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Evaluation, Preclinical
  • Half-Life
  • Heterografts / drug effects
  • Humans
  • Lenalidomide
  • Male
  • Mice, Inbred ICR
  • Mice, SCID
  • Multiple Myeloma / genetics
  • Multiple Myeloma / pathology*
  • Nuclear Proteins / chemistry
  • Osteoclasts / drug effects
  • Phthalimides / chemistry
  • Phthalimides / pharmacokinetics
  • Phthalimides / pharmacology*
  • Thalidomide / analogs & derivatives
  • Thalidomide / chemistry
  • Thalidomide / pharmacology

Substances

  • 2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3-dione
  • Nuclear Proteins
  • Phthalimides
  • nucleophosmin
  • Thalidomide
  • Lenalidomide

Grant support

This work was supported in part by a Grant-in-Aid for Scientific Research (Y. Hattori, MM) and a grant from the Private University Strategic Research Base Development Program (Y. Hattori) of MEXT (the Ministry of Education, Culture, Sports, Science and Technology) of Japan, Keio Gijuku Academic development Funds (Y. Hattori) and Japan Leukemia Research Fund (Y. Hattori, MM). The funders had no role in study design, data collection and analysis, decision to publish, or preparartion of the manuscript.