Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) is the most common mutation in patients with acute myeloid leukemia (AML). FLT3-ITD induces constitutive activation of FLT3, causing an abnormally rapid proliferation of cancer cells. In this study, we identified novel FLT3 inhibitors and investigated 5-(4-fluorophenyl)--phenyloxazol-2-amine (compound ; ) as candidates for the treatment of AML. The results showed that inhibited the activities of FLT3 and mutated FLT3 in a cell-free kinase assay and Molm-13 and MV4-11 cells, as well as the proliferation of FLT3-ITD AML cells, increasing apoptosis. The anti-leukemic activity of was confirmed by in vivo tumor growth inhibition in MV4-11 xenograft mice. Besides, suppressed the expression of DNA damage repair genes. Combination treatment with and olaparib (a poly (ADP-ribose) polymerase [PARP] inhibitor) synergistically inhibited cell proliferation in Molm-13 and MV4-11 cells. Our findings demonstrated that is a therapeutic candidate targeting FLT3 for AML treatment and suggested that combination treatment with and a PARP inhibitor may be an effective therapy regimen for FLT3-mutated AML.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663913 | PMC |
| http://dx.doi.org/10.3390/molecules25215154 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
An overview of small-molecule agents for the treatment of psoriasis.
Bioorg Med Chem
January 2025
Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong 510260, China. Electronic address:
Psoriasis is a prevalent, chronic inflammatory disease characterized by abnormal skin plaques. To date, physical therapy, topical therapy, systemic therapy and biologic drugs are the most commonly employed strategies for treating psoriasis. Recently, many agents have advanced to clinical trials, and some anti-psoriasis drugs have been approved, including antibody drugs and small-molecule drugs.
View Article and Find Full Text PDFPharmacologically induced proteolysis of histone deacetylase-6 attenuates influenza virus replication despite limited anti-tumor effects.
Life Sci
January 2025
Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. Electronic address:
The protein deacetylase HDAC6 has been controversially linked to cancer cell proliferation and viral propagation. We analyzed whether a pharmacological depletion of HDAC6 with a recent proteolysis-targeting chimera (PROTAC) kills tumor cells. We show that low micromolar doses of the cereblon-based PROTAC TH170, but not its inactive analog TH170E, induce proteasomal degradation of HDAC6.
View Article and Find Full Text PDFThe polypharmacy combination of the BCL-2 inhibitor venetoclax (VEN) and the FLT3 inhibitor gilteritinib (GIL) is more active in acute myeloid leukemia cells than novel polypharmacologic BCL-2/FLT3 VEN-GIL hybrid single-molecule inhibitors.
Eur J Med Chem
December 2024
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD, 21201, USA; University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, 22 S. Greene St., Baltimore, MD, 21201, USA. Electronic address:
Current treatments for acute myeloid leukemias (AMLs) cure fewer than 30 % of patients. This low efficacy is due, in part, to the inter-patient and intra-patient heterogeneity of AMLs; accordingly, all current AML treatment regimens involve drug combinations (polypharmacy). A recently-completed clinical trial in relapsed/refractory AML using a combination of two newer targeted antileukemics, the BCL-2 inhibitor venetoclax (VEN) plus the FLT3 inhibitor gilteritinib (GIL), yielded highly promising results for this two-drug polypharmacy combination.
View Article and Find Full Text PDFIdentification of possible drug treatment targets and related immune cell infiltration properties in acute myeloid leukemia utilizing robust rank aggregation algorithm.
Leuk Lymphoma
January 2025
Department of Oncology, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi, China.
In this study, we aimed to uncover novel biomarkers in acute myeloid leukemia (AML) that could serve as prognostic indicators or therapeutic targets. We analyzed AML microarray datasets from the Gene Expression Omnibus (GEO) repository, identifying key differentially expressed genes (DEGs) through the robust rank aggregation (RRA) approach. The functions of these DEGs were elucidated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses.
View Article and Find Full Text PDFAtypical B-Cell Acute Lymphoblastic Leukemia with iAMP21 in the Context of Constitutional Ring Chromosome 21: A Case Report and Review of the Genetic Insights.
Int J Mol Sci
January 2025
Centro de Investigación Biomédica en Red de Cáncer, CIBERONC CB16/12/00284, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Recent studies have demonstrated the association between constitutional ring chromosome 21 (r(21)c) and the development of B-cell acute lymphoblastic leukemia (B-ALL) with intrachromosomal amplification of chromosome 21 (iAMP21). iAMP21 acts as a driver which is often accompanied by secondary alterations that influence disease progression. Here, we report an atypical case of iAMP21 B-ALL with a unique molecular profile in the context of r(21)c.
View Article and Find Full Text PDFWant 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!