Abstract
Non-small-cell lung carcinoma (NSCLC) is one of the most common forms of lung cancer, and a leading cause of cancer death among human beings. There is an urgent demand for novel therapeutics for the treatment of NSCLC to enhance the efficacy of the currently applied Tyrosine kinase inhibitors (TKIs) therapy and to overcome therapy-resistance. Here, we report a novel small-molecule inhibitor that simultaneously targets histone deacetylase (HDAC) and macrophage migration inhibitory factor (MIF). The HDAC/MIF dual inhibitor proved to be toxic for EGFR mutated (H1650, TKI-resistant) or knock out (A549 EGFR−/−) NSCLC cell lines. Further experiments showed that HDAC inhibition inhibits cell survival and proliferation, while MIF inhibition downregulates pAKT or AKT expression level, which both interfere with cell survival. Furthermore, the combination treatment of TKI and HDAC/MIF dual inhibitor showed that the dual inhibitor enhanced TKI inhibitory efficacy, highlighting the advantages of HDAC/MIF dual inhibitor for more effective treatment of NSCLC.
Highlights
Over decades, drug discovery has focused on developing drugs with selectivity to a single target [1,2]
Our results showed that histone deacetylase (HDAC) inhibition suppressed cell survival and proliferation, while inhibition of migration inhibitory factor (MIF) interfered with the AKT pathway, influencing cell survival
The inhibitor retained the inhibitory prop erties for both HDAC and MIF inhibition to give a HDAC/MIF dual in hibitor that showed a better potency in cell toxicity in H1650 (EGFR mutated, Tyrosine kinase inhibitors (TKIs)-resistant) and EGFR knock out A549 cell lines
Summary
Drug discovery has focused on developing drugs with selectivity to a single target [1,2]. O-Aminoanilide-based in hibitors, such as tucidinostat, entinostat and tacedinaline (CI994), have shown potency to target class I HDACs selectively [15,16] These oaminoanilide-based class I HDAC inhibitors showed promising potency as multitargeting epigenetic agents [17,18], and in combination therapy for the treatment of cancer [19]. HDAC inhibitors, which provides opportunities for a more targeted interference with proliferation of cancer cells Considering this we anticipate that o-aminoanilide-based HDAC inhibitors have potential for treatment of NSCLC. The ZBG is the essential group for HDAC inhibition, because it coordinates to the catalytic Zn2+ ion in the active site of the enzyme Inspired by these features, a linked pharma cophore strategy would be an effective approach to design novel in hibitors against both targets and to test if dual inhibition provides enhanced effects. After examining the AKT pathway, we further applied a combination of afatinib and the HDAC/MIF dual inhibitor for a combination treatment of A549 cells
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