Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutants of the FLT3 receptor tyrosine kinase (RTK) with duplications in the juxtamembrane domain (FLT3-ITD) act as drivers of acute myeloid leukemia (AML). Potent tyrosine kinase inhibitors (TKi) of FLT3-ITD entered clinical trials and showed a promising, but transient success due to the occurrence of secondary drug-resistant AML clones. A further caveat of drugs targeting FLT3-ITD is the co-targeting of other RTKs which are required for normal hematopoiesis. This is observed quite frequently. Therefore, novel drugs are necessary to treat AML effectively and safely. Recently bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. In order to optimize these agents we synthesized novel derivatives of these methanones with various substituents. Methanone 16 and its carbamate derivative 17b inhibit FLT3-ITD at least as potently as the TKi AC220 (quizartinib). Models indicate corresponding interactions of 16 and quizartinib with FLT3. The activity of 16 is accompanied by a high selectivity for FLT3-ITD.
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PMID:A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia. 3219 35

Mutations in the FLT3 receptor tyrosine kinase are the most frequently found mutations in acute myeloid leukemia (AML). Patients with FLT3 internal tandem duplication (ITD) mutations have poor prognoses. The approved FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and gilteritinib improve survival in AML with FLT3 mutations. Multiple other FLT3 inhibitors are in clinical development. Patients frequently relapse after response to FLT3 inhibitors and the optimal use of FLT3 inhibitors in the upfront, relapse, and maintenance settings remain to be established. We will discuss the biology of FLT3, approved and investigational FLT3 inhibitors, resistance mechanisms, and emerging FLT3 TKI combination clinical trials.
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PMID:FLT3 Inhibition in Acute Myeloid Leukemia. 3286 67

Activating mutations in FLT3 receptor tyrosine kinase are found in a third of acute myeloid leukemia (AML) patients and are associated with disease relapse and a poor prognosis. The majority of these mutations are internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3, which have been validated as a therapeutic target. The clinical success of selective inhibitors targeting oncogenic FLT3, however, has been limited due to the acquisition of drug resistance. Herein the identification of a dual FLT3/microtubule polymerization inhibitor, chalcone 4 (2'-allyloxy-4,4'-dimethoxychalcone), is reported through screening of 15 related chalcones for differential antiproliferative activity in leukemia cell lines dependent on FLT3-ITD (MV-4-11) or BCR-ABL (K562) oncogenes and by subsequent screening for mitotic inducers in the HCT116 cell line. Three natural chalcones (1-3) were found to be differentially more potent toward the MV-4-11 (FLT3-ITD) cell line compared to the K562 (BCR-ABL) cell line. Notably, the new semisynthetic chalcone 4, which is a 2'-O-allyl analogue of the natural chalcone 3, was found to be more potent toward the FLT3-ITD+ cell line and inhibited FLT3 signaling in FLT3-dependent cells. An in vitro kinase assay confirmed that chalcone 4 directly inhibited FLT3. Moreover, chalcone 4 induced mitotic arrest in these cells and inhibited tubulin polymerization in both cellular and biochemical assays. Treatment of MV-4-11 cells with this inhibitor for 24 and 48 h resulted in apoptotic cell death. Finally, chalcone 4 was able to overcome TKD mutation-mediated acquired resistance to FLT3 inhibitors in a MOLM-13 cell line expressing FLT3-ITD with the D835Y mutation. Chalcone 4 is, therefore, a promising lead for the discovery of dual-target FLT3 inhibitors.
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PMID:Natural and Semisynthetic Chalcones as Dual FLT3 and Microtubule Polymerization Inhibitors. 3297 53

Acute myelogenous leukaemia (AML) is an aggressive blood cancer characterized by the rapid proliferation of immature myeloid blast cells, resulting in a high mortality rate. The 5-year overall survival rate for AML patients is approximately 25%. Circa 35% of all patients carry a mutation in the FLT3 gene which have a poor prognosis. Targeting FLT3 receptor tyrosine kinase has become a treatment strategy in AML patients possessing FLT3 mutations. The most common mutations are internal tandem duplications (ITD) within exon 14 and a single nucleotide polymorphism (SNP) that leads to a point mutation in the D835 of the tyrosine kinase domain (TKD). Variations in the ITD sequence and the occurrence of other point mutations that lead to ligand-independent FLT3 receptor activation create difficulties in developing personalized therapeutic strategies to overcome observed mutation-driven drug resistance. Midostaurin and quizartinib are tyrosine kinase inhibitors (TKIs) with inhibitory efficacy against FLT3-ITD, but exhibit limited clinical impact. In this review, we focus on the structural aspects of the FLT3 receptor and correlate those mutations with receptor activation and the consequences for molecular and clinical responsiveness towards therapies targeting FLT3-ITD positive AML.
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PMID:Pharmacological impact of FLT3 mutations on receptor activity and responsiveness to tyrosine kinase inhibitors. 3324 49


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