AUTHOR=Chen Yiming , Feng Jinhong , Hu Yajie , Wang Xuejian , Song Weiguo , Zhang Lei 

TITLE=Discovery of N-(2-Amino-4-Fluorophenyl)-4-[bis-(2-Chloroethyl)-Amino]-Benzamide as a Potent HDAC3 Inhibitor

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.592385

DOI=10.3389/fonc.2020.592385

ISSN=2234-943X

ABSTRACT=<p>In discovery of HDAC inhibitors with improved activity and selectivity, fluorine substitution was performed on our previously derived lead compound. The synthesized molecules N-(2-amino-4-fluorophenyl)-4-[<italic>bis</italic>-(2-chloroethyl)-amino]-benzamide (FNA) exhibited class I (HDAC1, 2, and 3) selectivity in the <italic>in vitro</italic> enzymatic assay and especially potent against HDAC3 activity (IC<sub>50</sub>: 95.48 nM). The results of <italic>in vitro</italic> antiproliferative assay indicated that FNA exhibited solid tumor cell inhibitory activities with IC<sub>50</sub> value of 1.30 μM against HepG2 cells compared with SAHA (17.25 μM). Moreover, the <italic>in vivo</italic> xenograft model study revealed that FNA could inhibit tumor growth with tumor growth inhibition (TGI) of 48.89% compared with SAHA (TGI of 48.13%). Further HepG2 cell–based apoptosis and cell cycle studies showed that promotion of apoptosis and G2/M phase arrest make contributions to the antitumor activity of FNA. In addition, drug combination results showed that 0.5 μM of FNA could improve the anticancer activity of taxol and camptothecin. The present studies revealed the potential of FNA utilized as a high potent lead compound for further discovery of isoform selective HDAC inhibitors.</p>