硼替佐米
化学
多发性骨髓瘤
蛋白酶体抑制剂
蛋白酶体
IC50型
组蛋白脱乙酰基酶
药理学
癌症研究
组蛋白
体外
生物化学
内科学
生物
医学
基因
作者
Yi Zhou,Xiaoting Liu,Junxin Xue,Lulu Liu,Liang Tao,Wen Li,Yang Xia,Xuben Hou,Hao Fang
标识
DOI:10.1021/acs.jmedchem.9b02161
摘要
While proteasome inhibitors such as bortezomib showed satisfactory clinical benefits in the initial treatment of multiple myeloma (MM), drug resistance and relapse are unavoidable. Recent studies suggested inhibition of histone deacetylases (HDACs) restored sensitivity of bortezomib-resistant MM. Hence, we designed dual inhibitors targeting both HDACs and proteasomes to address the resistance of bortezomib. The most potent inhibitors, ZY-2 and ZY-13 showed excellent inhibition against proteasome and good selectivity against HDACs. In particular, ZY-2 not only exhibited good antiproliferative activities on the MM cell lines RPMI-8226, U266, and KM3 (IC50 values of 6.66, 4.31, and 10.1 nM, respectively) but also showed more potent antiproliferative activities against the bortezomib-resistant MM cell line KM3/BTZ compared with bortezomib (IC50 values of 8.98 vs. 226 nM, P < 0.01) and even better than the combination of the HDAC inhibitor MS-275 and bortezomib (1:1) (IC50 values of 8.98 vs. 98.0 nM, P < 0.01).
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