Design, synthesis and biological evaluation of novel 1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolins as potential EZH2 inhibitors

Abstract

This study led to the discovery of several potent compounds with low nanomolar to sub-nanomolar potency for EZH2.

Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer

“…Recently, several EZH2 small molecule inhibitors were discovered, and these compounds are structurally related to the pyridones 23 24 25 26 . We previously designed and synthesized numerous compounds based on a pyridone-containing chemical scaffold 22 using classical medicinal chemistry to identify EZH2 small molecule inhibitors, and ZLD1039 ( Fig. 1a ) was selected as the lead compound for its desirable potency and physicochemical properties.…”

“…No further authentication was conducted for the tumor cell lines. ZLD1039 was synthesized at the State Key of Laboratory of Biotherapy (Sichuan University, Sichuan, China) 22 .…”

“…However, no orally bioavailable inhibitors of EZH2 have been used in breast cancer in vivo models. Here, we developed ZLD1039, a novel potent and selective inhibitor of EZH2 22 , which inhibited the methyltransferase activity of EZH2 with high selectivity across an HMT panel. ZLD1039-treated breast cancer cells exhibited decreased H3K27me3 and H3K27me2 without changes in EZH2 and other H3 methylation markers.…”

Discovery of quinolone derivatives as antimycobacterial agents

“…Acetylation of the intermediate enamines to the corresponding ketones was then carried out in the presence of triethylamine at À5 C. The title compounds 6a1-6a2, 6b1-6b36, 6c1 and 6d1-6d13 were synthesized via the pathway shown in Scheme 2. The compounds 4a-4d were synthesized by cyclizing the intermediates 3a-3b using 2-cyanoacetamide and triethylenediamine at 40 C for 10 h. 22 The mixture of 4b and 4d was dissolved in ethanol and stirred and reuxed for more than 1 h. Solids in the reaction mixture were ltered and then washed with hot ethanol while the solution was hot. Pure 4b and 4d were obtain before above solids washed several times.…”

ZLD1122, a novel EZH2 and EZH1 small molecular inhibitor, blocks H3K27 methylation and diffuse large B cell lymphoma cell growth

“…Our laboratory developed a novel EZH2 and EZH1 smallmolecule inhibitor, 5-(cyclohexyl(ethyl)amino)-N-((1,7-dimethyl-3oxo-2,3,5,6,7,8-hexahydroisoquinolin-4-yl)methyl)-4-methyl-4 0 -((4methylpiperazin-1-yl)methyl)biphenyl-3-carboxamide (ZLD1122), 14 which signicantly inhibited EZH1 and EZH2 activities among a panel of HMTs. Moreover, ZLD1122 inhibited a diverse panel of cancer cell lines, among which NHL cells were most sensitive to ZLD1122.…”