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鉴定一种新型的 c-Myc 抑制剂,对多发性骨髓瘤细胞具有抗肿瘤作用。

Identification of a novel c-Myc inhibitor with antitumor effects on multiple myeloma cells.

机构信息

Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.

Department of Hematology, The Affliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.

出版信息

Biosci Rep. 2018 Sep 19;38(5). doi: 10.1042/BSR20181027. Print 2018 Oct 31.

Abstract

Increasing evidence shows that c-Myc oncoprotein is tightly associated with multiple myeloma (MM) progression. Herein, we identified compound 7594-0035, which is a novel inhibitor that specifically targets c-Myc. It was identified from the ChemDiv compound database by molecular docking-based, high-throughput virtual screening. Compound 7594-0035 inhibited MM cell proliferation , induced cell cycle G-phase arrest, and triggered MM cell death by disturbing the stability of c-Myc protein. Additionally, we also found that compound 7594-0035 overcame bortezomib (BTZ) drug resistance and increased the killing effect on MM cells in combination with BTZ. The severe combined immune deficiency (SCID) mouse xenograft model revealed that compound 7594-0035 partially decreased the primary tumor growth of Roswell Park Memorial Institute (RPMI)-8226 cells The novel small molecular compound 7594-0035 described in the present study that targets c-Myc protein is likely to be a promising therapeutic agent for relapsed/refractory MM.

摘要

越来越多的证据表明,c-Myc 癌蛋白与多发性骨髓瘤(MM)的进展密切相关。在此,我们鉴定了化合物 7594-0035,这是一种专门针对 c-Myc 的新型抑制剂。它是通过基于分子对接的高通量虚拟筛选从 ChemDiv 化合物数据库中鉴定出来的。化合物 7594-0035 通过干扰 c-Myc 蛋白的稳定性,抑制 MM 细胞增殖、诱导细胞周期 G 期阻滞,并触发 MM 细胞死亡。此外,我们还发现化合物 7594-0035 可以克服硼替佐米(BTZ)耐药性,并与 BTZ 联合使用增加对 MM 细胞的杀伤作用。严重联合免疫缺陷(SCID)小鼠异种移植模型表明,化合物 7594-0035 部分减少了 RPMI-8226 细胞的原发性肿瘤生长。本研究中描述的靶向 c-Myc 蛋白的新型小分子化合物 7594-0035 可能是一种有前途的复发性/难治性 MM 治疗药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f73/6146296/68690577c03e/bsr-38-bsr20181027-g1.jpg

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