Design, Synthesis, and Biological Evaluation of Novel Fms-Like Tyrosine Kinase 3/VEGFR2/Histone Deacetylase Inhibitors for the Treatment of Acute Myeloid Leukemia
Hua TianYichen LiuSongwen LinJialing DengQinghua ZhangFeng HaoYao TangTianning XiongKehui ZhangGe ShiLijun LuoShouguo PengSheng LiMing JiHeng Xu
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The concurrent targeting of Fms-like tyrosine kinase 3 (FLT3)/VEGFR2/Histone deacetylase (HDAC) represents a novel and promising therapeutic strategy for acute myeloid leukemia. In this work, we hybridized essential pharmacophores from sorafenib and SAHA (vorinostat) and then conducted structure–activity relationship studies to identify two lead compounds 26 and 32 that potently inhibit FLT3, VEGFR2, and HDAC in a nanomolar range. In cell evaluation, compounds 26 and 32 exhibited potent proliferative activities against a panel of leukemia cells including MV4-11 and MOLM-13. Western blotting analysis also showed that compounds 26 and 32 suppressed the phosphorylation of FLT3, STAT3, and ERK1/2 and increased histone H3 acetylation in a dose-dependent manner, indicating the effective inhibition of FLT3, VEGFR2, and HDAC. Supported by its pharmacokinetic properties, compound 26 showed remarkable anticancer efficacy in a MV4-11 xenograft model. Additionally, it demonstrated superior efficacy compared to midostaurin and gilteritinib in the Ba/F3-FLT3-ITD-N701K xenograft model.Keywords:
HDAC8
We previously identified 3-hydroxypyridine-2-thione (3HPT) as a novel zinc binding group for histone deacetylase (HDAC) inhibition. Early structure-activity relationship (SAR) studies led to various small molecules possessing selective inhibitory activity against HDAC6 or HDAC8 but devoid of HDAC1 inhibition. To delineate further the depth of the SAR of 3HPT-derived HDAC inhibitors (HDACi), we have extended the SAR studies to include the linker region and the surface recognition group to optimize the HDAC inhibition. The current efforts resulted in the identification of two lead compounds, 10d and 14e, with potent HDAC6 and HDAC8 activities that are inactive against HDAC1. These new HDACi possess anticancer activities against various cancer cell lines including Jurkat J.γ1 for which SAHA and the previously disclosed 3HPT-derived HDACi were inactive.
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Approximately five million United States (U.S.) adults are diagnosed with heart failure (HF), with eight million U.S. adults projected to suffer from HF by 2030. With five-year mortality rates following HF diagnosis approximating 50%, novel therapeutic treatments are needed for HF patients. Pre-clinical animal models of HF have highlighted histone deacetylase (HDAC) inhibitors as efficacious therapeutics that can stop and potentially reverse cardiac remodeling and dysfunction linked with HF development. HDACs remove acetyl groups from nucleosomal histones, altering DNA-histone protein electrostatic interactions in the regulation of gene expression. However, HDACs also remove acetyl groups from non-histone proteins in various tissues. Changes in histone and non-histone protein acetylation plays a key role in protein structure and function that can alter other post translational modifications (PTMs), including protein phosphorylation. Protein phosphorylation is a well described PTM that is important for cardiac signal transduction, protein activity and gene expression, yet the functional role for acetylation-phosphorylation cross-talk in the myocardium remains less clear. This review will focus on the regulation and function for acetylation-phosphorylation cross-talk in the heart, with a focus on the role for HDACs and HDAC inhibitors as regulators of acetyl-phosphorylation cross-talk in the control of cardiac function.
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Histone deacetylase 5
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The therapeutic landscape of CML has rapidly evolved since the introduction of imatinib into clinical practice and patients are expected to have a near normal life expectancy. In the era of second or third-generation tyrosine kinase inhibitors (TKIs), a personalized treatment strategy for individual patients considering comorbidities, tolerability, disease phase and goals of therapy has become the standard of care. Though newer TKIs have a definite role in the treatment of resistant disease, despite achieving quicker and deeper molecular responses no survival improvement is obtained in the front-line setting compared to imatinib. This chapter review is focused on the role of imatinib, the first targeted treatment for CML in the era of novel TKI therapy.
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Invention of imatinib was a great step for much more successful clinical management of chronic myeloid leukemia (CML).Now, two other tyrosine kinase inhibitors (TKIs) are available both for first-line and later treatments of CML.In Turkey, currently 2nd line TKIs are indicated only for imatinib failure.This review will evaluate indications for changing imatinib with dasatinib or nilotinib, success of the 2nd line agents in the second-line treatment and some important properties of these agents.
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In the present study, a novel series of 11 urushiol-based hydroxamic acid histone deacetylase (HDAC) inhibitors was designed, synthesized, and biologically evaluated. Compounds 1-11 exhibited good to excellent inhibitory activities against HDAC1/2/3 (IC50 : 42.09-240.17 nM) and HDAC8 (IC50 : 16.11-41.15 nM) in vitro, with negligible activity against HDAC6 (>1409.59 nM). Considering HDAC8, docking experiments revealed some important features contributing to inhibitory activity. According to Western blot analysis, select compounds could notably enhance the acetylation of histone H3 and SMC3 but not-tubulin, indicating their privileged structure is appropriate for targeting class I HDACs. Furthermore, antiproliferation assays revealed that six compounds exerted greater in vitro antiproliferative activity against four human cancer cell lines (A2780, HT-29, MDA-MB-231, and HepG2, with IC50 values ranging from 2.31-5.13 μM) than suberoylanilide hydroxamic acid; administration of these compounds induced marked apoptosis in MDA-MB-231 cells, with cell cycle arrest in the G2/M phase. Collectively, specific synthesized compounds could be further optimized and biologically explored as antitumor agents.
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The histone deacetylase (HDAC) enzyme plays an important role in gene transcription. Inhibitors of histone deacetylases induce cell differentiation and suppress cell proliferation in tumor cells. Hydroxamates with rigid linker have displayed better inhibition profiles than those with linear and flexible aliphatic linkers. We have designed and synthesized several potential histone deacetylase inhibitors with a piperazine moiety in the linker region to test the effect of reduced linker flexibility. Inhibitors were evaluated for their inhibitory action on human HDAC3/NCoR2 and HDAC8. N-Hydroxycarboxamide derivatives (compounds 4a-d) were found to be better than N-hydroxyacetamide derivatives (compounds 6a-d) against HDAC8. Amongst the synthesized compounds, 4a (HDAC8, IC50: 3.15 microM) with no substitution in the aryl cap was the most active and promising lead for further investigations.
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During therapy with second generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia, a number of patients demonstrate non-hematological toxicity of various degrees. The article contains review of references about second generation tyrosine kinase inhibitors effect on the frequency of cardiovascular and metabolic problems.
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