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Updated: Aug 19, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
The anti-leukemic efficacy of the third generation bisphosphonate ONO5920/YM529
Hidekazu Segawa1, Shinya Kimura, Junya Kuroda
1Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara Shogoin Sakyo-ku, Kyoto 606-8507, Japan.
Abstract:
Ras proteins are frequently over-expressed in leukemia and contribute to leukemogenesis. We evaluated the anti-leukemic efficacy of a new third-generation bisphosphonate, ONO5920/YM529 (YM529). YM529 prevents the prenylation of Ras proteins and inhibited the growth of leukemic cells including a P-glycoprotein (P-gp) over-expressing cell line in a concentration- and time-dependent manner by inducing apoptosis in vitro. Moreover, YM529 synergistically augmented the anti-leukemic activities of paclitaxel and daunorubicin in vitro. Importantly, YM529 prolonged the survival of NOD/SCID mice engrafted with human primary leukemic cells. These findings indicate that the YM529 may become a novel molecular therapeutic class for treatment of leukemias.
Insights
A novel bisphosphonate, ONO5920/YM529 (YM529), shows anti-leukemic effects by inhibiting Ras protein prenylation. This compound demonstrated efficacy in vitro and in vivo, suggesting potential as a new leukemia therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ras proteins are frequently over-expressed in leukemia, driving leukemogenesis.
- There is a need for novel therapeutic agents targeting leukemia, particularly those overcoming drug resistance.
Purpose of the Study:
- To evaluate the anti-leukemic efficacy of the third-generation bisphosphonate ONO5920/YM529 (YM529).
- To investigate the mechanism of action of YM529, including its effect on Ras protein prenylation and its synergistic potential with existing chemotherapeutics.
Main Methods:
- In vitro assessment of YM529's effect on leukemic cell growth, including P-glycoprotein (P-gp) over-expressing lines.
- Evaluation of YM529's ability to induce apoptosis and its synergistic effects with paclitaxel and daunorubicin.
- In vivo studies using NOD/SCID mice engrafted with human primary leukemic cells to assess survival benefits.
Main Results:
- YM529 inhibited leukemic cell growth in a concentration- and time-dependent manner by inducing apoptosis.
- YM529 demonstrated efficacy against a P-gp over-expressing cell line, suggesting potential in overcoming drug resistance.
- YM529 synergistically enhanced the anti-leukemic activities of paclitaxel and daunorubicin in vitro.
- YM529 significantly prolonged the survival of mice engrafted with human leukemic cells.
Conclusions:
- YM529 exhibits significant anti-leukemic activity through inhibition of Ras protein prenylation and induction of apoptosis.
- YM529 shows promise as a novel therapeutic agent for leukemia, potentially overcoming drug resistance and augmenting existing therapies.
- These findings support the development of YM529 as a novel molecular therapeutic class for leukemia treatment.
