AI Article Synopsis
- FLT3-ITD and TKD mutants are key drivers in acute myeloid leukemia (AML), making FLT3 a promising target for new treatments.
- To identify next-generation FLT3 inhibitors, researchers modified G-749 and found that a derivative named MY-10 showed strong and selective inhibition against FLT3-ITD and FLT3-D835Y mutants.
- MY-10 was effective in blocking cell cycle progression, inducing apoptosis, and reducing harmful reactive oxygen species, while not affecting c-KIT kinase, suggesting its potential as a targeted ACML therapy.
Article Abstract
FLT3-ITD and TKD mutants play a central role in acute myeloid leukemia (AML), making FLT3 an attractive target for AML treatment. To discover next-generation FLT3 inhibitors and gather additional structure-activity relationship (SAR) information, we performed structural modifications of G-749 (denfivontinib) utilizing structure simplification and scaffold hopping strategies. Among these derivatives, MY-10 exhibited the most potent and selective inhibition of MV4-11 cell proliferation, demonstrating potent inhibitory activity against FLT3-ITD (IC = 6.5 nM) and FLT3-D835Y (IC = 10.3 nM) mutants. Notably, MY-10 exhibited no inhibitory activity against c-KIT kinase (IC > 100 μM). Mechanistic studies revealed that MY-10 arrested the cell cycle at the G0/G1 phase and efficiently induced apoptosis. Furthermore, it significantly reduced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP), and strongly inhibited FLT3-mediated signaling pathways. These findings, along with the obtained SAR information, provide valuable insights for the further development of FLT3 inhibitors.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2024.130082 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Advances and Challenges in Quizartinib-Based FLT3 Inhibition for Acute Myeloid Leukemia: Mechanisms of Resistance and Prospective Combination Therapies.
Eur J Haematol
January 2025
Hematology Unit, Azienda Ospedaliera Annunziata, Cosenza, Italy.
FLT3 mutations are among the most common genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Significant advancements have been made in developing FLT3 inhibitors (FLT3Is), such as quizartinib, which have improved treatment outcomes in both newly diagnosed and relapsed/refractory AML. Resistance to FLT3Is remains a major clinical challenge, driven by diverse mechanisms including FLT3 point mutations, cellular escape pathways, and the influence of the bone marrow microenvironment.
View Article and Find Full Text PDFFLT3 Inhibitors Induce p53 Instability, Driven by STAT5/MDM2/p53 Competitive Interactions in Acute Myeloid Leukemia.
Cancer Lett
January 2025
Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China. Electronic address:
Article Synopsis
- FLT3 mutations are common in AML, making them a key target for therapy, but resistance to FLT3 inhibitors is a significant challenge.
- Tyrosine kinase inhibitors (TKIs) promote p53 degradation in FLT3-ITD AML cells through mechanisms involving STAT5 and MDM2, disrupting p53's role as a tumor suppressor.
- Using MDM2 inhibitors alongside TKIs can stabilize p53 levels, enhancing the effectiveness of treatments and suggesting a promising combination approach for AML therapy.
Targeting FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia: Novel molecular approaches and therapeutic challenges.
Biomed Pharmacother
December 2024
Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove 500 05, Czech Republic. Electronic address:
Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy, has generally a poor prognosis despite the recent advancements in diagnostics and treatment. Genetic instability, particularly mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, is associated with severe outcomes. Approximately 30 % of AML patients harbor FLT3 mutations, which have been linked to higher relapse and reduced survival rates.
View Article and Find Full Text PDFRevealing the heterogeneity of treatment resistance in less-defined subtype diffuse large B cell lymphoma patients by integrating programmed cell death patterns and liquid biopsy.
Clin Transl Med
January 2025
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.
Precision medicine in less-defined subtype diffuse large B-cell lymphoma (DLBCL) remains a challenge due to the heterogeneous nature of the disease. Programmed cell death (PCD) pathways are crucial in the advancement of lymphoma and serve as significant prognostic markers for individuals afflicted with lymphoid cancers. To identify robust prognostic biomarkers that can guide personalized management for less-defined subtype DLBCL patients, we integrated multi-omics data derived from 339 standard R-CHOP-treated patients diagnosed with less-defined subtype DLBCL from three independent cohorts.
View Article and Find Full Text PDFStrategies for the treatment of acute myeloid leukemia with FLT3 mutations: a patent review.
Expert Opin Ther Pat
January 2025
Biomedical Research Centre, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.
Introduction: Approximately one-third of all AML patients have a mutation in the () gene, which is associated with a poor prognosis in these individuals. The 2017 approval of midostaurin, the first FLT3 inhibitor, spurred extensive development of more potent and selective inhibitors with an improved safety profile.
Areas Covered: This review analyzes patent inventions for the treatment of AML using FLT3 inhibitors, covering developments from the earliest to the most recent, disclosed in 2024.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!