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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
A cell competition-based small molecule screen identifies a novel compound that induces dual c-Myc depletion and p53
Dagim Shiferaw Tadele1, Joseph Robertson1, Richard Crispin1
1Department of Molecular Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.
Abstract:
Breakpoint Cluster Region-Abelson kinase (BCR-Abl) is a driver oncogene that causes chronic myeloid leukemia and a subset of acute lymphoid leukemias. Although tyrosine kinase inhibitors provide an effective treatment for these diseases, they generally do not kill leukemic stem cells (LSCs), the cancer-initiating cells that compete with normal hematopoietic stem cells for the bone marrow niche. New strategies to target cancers driven by BCR-Abl are therefore urgently needed. We performed a small molecule screen based on competition between isogenic untransformed cells and BCR-Abl-transformed cells and identified several compounds that selectively impair the fitness of BCR-Abl-transformed cells. Interestingly, systems-level analysis of one of these novel compounds, DJ34, revealed that it induced depletion of c-Myc and activation of p53. DJ34-mediated c-Myc depletion occurred in a wide range of tumor cell types, including lymphoma, lung, glioblastoma, breast cancer, and several forms of leukemia, with primary LSCs being particularly sensitive to DJ34. Further analyses revealed that DJ34 interferes with c-Myc synthesis at the level of transcription, and we provide data showing that DJ34 is a DNA intercalator and topoisomerase II inhibitor. Physiologically, DJ34 induced apoptosis, cell cycle arrest, and cell differentiation. Taken together, we have identified a novel compound that dually targets c-Myc and p53 in a wide variety of cancers, and with particularly strong activity against LSCs.
Insights
A novel compound, DJ34, effectively targets leukemic stem cells (LSCs) by depleting c-Myc and activating p53. This discovery offers a promising new strategy for treating BCR-Abl-driven cancers, including leukemia.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Breakpoint Cluster Region-Abelson kinase (BCR-Abl) drives chronic myeloid leukemia and acute lymphoid leukemias.
- Current tyrosine kinase inhibitors often fail to eliminate crucial leukemic stem cells (LSCs).
- Novel therapeutic strategies targeting BCR-Abl-driven cancers, particularly LSCs, are urgently needed.
Purpose of the Study:
- To identify novel compounds that selectively impair the fitness of BCR-Abl-transformed cells.
- To investigate the mechanism of action and therapeutic potential of identified compounds, specifically DJ34.
- To evaluate the efficacy of DJ34 against leukemic stem cells and various cancer types.
Main Methods:
- Small molecule screening using isogenic cell competition assays.
- Systems-level analysis of compound DJ34, including c-Myc and p53 modulation.
- Assessment of DJ34's effects on cancer cell transcription, DNA interaction, and physiological responses (apoptosis, cell cycle arrest, differentiation).
Main Results:
- A novel compound, DJ34, was identified that selectively impairs BCR-Abl-transformed cells.
- DJ34 induces c-Myc depletion and p53 activation across diverse cancer types, including primary LSCs.
- DJ34 acts as a DNA intercalator and topoisomerase II inhibitor, interfering with c-Myc transcription and inducing apoptosis, cell cycle arrest, and differentiation.
Conclusions:
- DJ34 is a novel compound with dual targeting of c-Myc and p53.
- DJ34 demonstrates potent activity against leukemic stem cells and a broad range of cancers.
- This compound represents a promising new therapeutic avenue for BCR-Abl-driven malignancies and other cancers.
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