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Updated: Nov 2, 2025
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Transcriptional drug repositioning and cheminformatics approach for differentiation therapy of leukaemia cells
Yasaman KalantarMotamedi1, Fatemeh Ejeian2, Faezeh Sabouhi2,3
1Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Abstract:
Differentiation therapy is attracting increasing interest in cancer as it can be more specific than conventional chemotherapy approaches, and it has offered new treatment options for some cancer types, such as treating acute promyelocytic leukaemia (APL) by retinoic acid. However, there is a pressing need to identify additional molecules which act in this way, both in leukaemia and other cancer types. In this work, we hence developed a novel transcriptional drug repositioning approach, based on both bioinformatics and cheminformatics components, that enables selecting such compounds in a more informed manner. We have validated the approach for leukaemia cells, and retrospectively retinoic acid was successfully identified using our method. Prospectively, the anti-parasitic compound fenbendazole was tested in leukaemia cells, and we were able to show that it can induce the differentiation of leukaemia cells to granulocytes in low concentrations of 0.1 μM and within as short a time period as 3 days. This work hence provides a systematic and validated approach for identifying small molecules for differentiation therapy in cancer.
Insights
This study introduces a new bioinformatics and cheminformatics method to find cancer differentiation therapy drugs. Fenbendazole was identified as a potential treatment, effectively differentiating leukemia cells in just 3 days.
Area of Science:
- Oncology
- Pharmacology
- Bioinformatics
Background:
- Differentiation therapy offers a targeted approach to cancer treatment, with retinoic acid successfully used for acute promyelocytic leukemia (APL).
- There is a significant need for novel small molecules to induce cancer cell differentiation across various cancer types, including leukemia.
Purpose of the Study:
- To develop and validate a novel transcriptional drug repositioning approach for identifying compounds for cancer differentiation therapy.
- To prospectively identify and test new drug candidates for leukemia differentiation.
Main Methods:
- A drug repositioning strategy integrating bioinformatics and cheminformatics was developed.
- The approach was validated retrospectively by identifying retinoic acid for leukemia.
- Fenbendazole, an anti-parasitic drug, was prospectively tested on leukemia cells.
Main Results:
- The developed method successfully identified retinoic acid in a retrospective validation.
- Fenbendazole demonstrated the ability to induce differentiation of leukemia cells into granulocytes.
- Effective differentiation was observed at low fenbendazole concentrations (0.1 μM) within 3 days.
Conclusions:
- The study presents a systematic and validated computational approach for discovering small molecules for differentiation therapy.
- Fenbendazole emerges as a promising candidate for leukemia differentiation therapy, warranting further investigation.
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