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Issue 33, 2015
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Design, synthesis and biological evaluation of novel 1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolins as potential EZH2 inhibitors

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Abstract

The histone lysine methyltransferase EZH2 has been implicated as a key component in cancer aggressiveness, metastasis and poor prognosis. This study discovered a new class of hexahydroisoquinolin derivatives as EZH2 inhibitors. A structure–activity relationship study showed that the steric hindrance was important to the activity for EZH2. A preliminary optimization study led to the discovery of several potent compounds with low nanomolar to sub-nanomolar potency for EZH2. Biological evaluation indicated that SKLB1049 was a highly potent with improved solubility compared to EPZ6438, SAM-competitive, and cell-active EZH2 inhibitor that decreased global H3K27me3 in SU-DHL-6 and Pfeiffer lymphoma cells in a concentration- and time-dependent manner. Further study indicated that SKLB1049 caused cell arrest in G0/G1 phase. These compounds would be useful as chemical tools to further explore the biology of EZH2 and provided us with a start point to develop new EZH2 inhibitors.

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

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Publication details

The article was received on 06 Feb 2015, accepted on 04 Mar 2015 and first published on 04 Mar 2015


Article type: Paper
DOI: 10.1039/C5RA02365C
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Citation: RSC Adv., 2015,5, 25967-25978

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

    L. Zhang, X. Song, N. Wang, L. Zhao, Q. Feng, X. You, C. Peng, T. Gao, M. Xiong, B. He, C. Gao, Y. Luo, Y. Xu, Q. Zhang and L. Yu, RSC Adv., 2015, 5, 25967
    DOI: 10.1039/C5RA02365C

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