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A novel phthalimide derivative, TC11, has preclinical effects on high-risk myeloma cells and osteoclasts
Maiko Matsushita1, Yoshie Ozaki1, Yuka Hasegawa1
1Clinical Physiology and Therapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan.
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.
Insights
A novel phthalimide derivative, TC11, shows significant anti-myeloma effects in vitro and in vivo, potentially benefiting high-risk multiple myeloma patients. TC11 also inhibits osteoclast activity, suggesting a dual therapeutic approach for bone lesions.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Multiple myeloma (MM) patients with high-risk cytogenetic abnormalities face poor prognoses despite recent treatment advances.
- Novel therapeutic strategies are crucial for improving outcomes in these challenging cases.
Purpose of the Study:
- To characterize a novel phthalimide derivative, TC11, for its potential efficacy against high-risk multiple myeloma.
- To evaluate TC11's anti-myeloma activity, pharmacokinetics, and anti-osteoclastogenic effects.
Main Methods:
- In vitro and in vivo studies using human myeloma-bearing SCID mice.
- Pharmacokinetic analysis in mice.
- Mouse osteoclast cultures treated with M-CSF and RANKL.
- Immunohistochemistry and molecular analyses.
Main Results:
- TC11 significantly delayed tumor growth and induced apoptosis in MM cells in vivo.
- Pharmacokinetics showed a Cmax of 2.1 μM and a half-life of 1.2 h.
- TC11 inhibited osteoclast differentiation and function.
- TC11 induced myeloma cell apoptosis via α-tubulin fragmentation and bound to NPM1.
Conclusions:
- TC11 demonstrates potent anti-myeloma and anti-osteoclastogenic activities, making it a promising candidate for high-risk MM, especially with bone involvement.
- TC11's molecular interactions, including binding to NPM1, warrant further investigation.
- These findings support the development of novel thalidomide derivatives for MM treatment.
