European Journal of Medicinal Chemistry (2021)
Update date:2022-07-29
Topics:
Cong, Zhanqing
Fu, Xuhong
Geng, Meiyu
Han, Xu
Huang, Xun
Li, Chunpu
Li, Cong
Li, Jia
Li, Xingjun
Lian, Fulin
Liu, Hong
Shi, Qiongyu
Su, Mingbo
Wang, Jiang
Wang, Shuni
Wei, Rongrui
Yang, Hong
Zhang, Naixia
Zheng, Xingling
Zhou, Yubo
Approximately 20% of multiple myeloma (MM) are caused by a chromosomal translocation t (4; 14) that leads to the overexpression of the nuclear receptor binding SET domain-protein 2 (NSD2) histone methyltransferase. NSD2 catalyzes the methylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Using high-throughput screening (HTS) with biological analyses, a series of 5-aminonaphthalene derivatives were designed and synthesized as novel NSD2 inhibitors. Among all the prepared compounds, 9c displayed a good NSD2 inhibitory activity (IC50 = 2.7 μM) and selectivity against both SET-domain-containing and non-SET-domain-containing methyltransferases. Preliminary research indicates the inhibition mechanism of compound 9c by significantly suppressed the methylation of H3K36me2. Compound 9c specifically inhibits the proliferation of the human B cell precursor leukemia cell line RS4:11 and the human myeloma cell line KMS11 by inducing cell cycle arrest and apoptosis with little cytotoxicity. It has been reported that the anti-cancer effect of compound 9c is partly achieved by completely suppressing the transcriptional activation of NSD2-targeted genes. When administered intraperitoneally at 25 mg/kg, compound 9c suppressed the tumor growth of RS4:11 xenografts in vivo and no body weight loss was detected in the tested SCID mice.
View MoreSEA BRGIHT INDUSTRY CO.,LIMITED
Contact:0086 755 8622 3990
Address:Rm 17B3,GuangCaiXinTianDi Bldg,GuiMiao Rd,NanShan District,Shenzhen,China
Neworld Chemical Co., Ltd Shanghai(expird)
Contact:+86-21-62202658
Address:11F, Blvd 2, No. 1969 PuXing Rd, Shanghai
Tianjin Bright Future Technology Co., Ltd
Contact:0086-22-58016666
Address:NO.136 DongTeng Lake Street Tianjin Economic and Technology Development Area,Tainjin,China
Shandong Xinke Petrochemical Co., Ltd.
Contact:+86-546-7277016
Address:Gudao Industrial Park, Hekou District, Dongying, Shandong Province, China
Contact:+86-21-38228826
Address:Room 505 Building 2, No 3377 Kangxin Highway, Shanghai, Republic China
Doi:10.1246/bcsj.49.3558
(1976)Doi:10.1080/00397911.2016.1194997
(2016)Doi:10.1080/10426500701693420
(2008)Doi:10.1080/10426500801968011
(2008)Doi:10.1002/jps.2600770521
(1988)Doi:10.1007/BF00479380
(1987)