HDAC/MIF dual inhibitor inhibits NSCLC cell survival and proliferation by blocking the AKT pathway

Fangyuan Cao, Zhangping Xiao, Siwei Chen, Chunlong Zhao, Deng Chen, Hidde J Haisma, Frank J Dekker*

*Corresponding author for this work

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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.

Original languageEnglish
Article number105396
Number of pages8
JournalBioorganic Chemistry
Early online date2021
Publication statusPublished - Dec-2021

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