Design, synthesis, and bioactivity evaluation of novel Bcl-2/HDAC dual-target inhibitors for the treatment of multiple myeloma.
Design, synthesis, and bioactivity evaluation of novel Bcl-2/HDAC dual-target inhibitors for the treatment of multiple myeloma.
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DOI：
10.1016/j.bmcl.2018.12.052
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发表时间：
2019-02
影响因子：
2.7
通讯作者：
R. Zhou;Shaoyu Fang;Min-min Zhang;Qingsen Zhang;Jian Hu;Mingping Wang;Chongqing Wang;Ju Zhu;Ai-jun Shen;Xin Chen;Canhui Zheng
中科院分区：
文献类型：
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作者：
R. Zhou;Shaoyu Fang;Min-min Zhang;Qingsen Zhang;Jian Hu;Mingping Wang;Chongqing Wang;Ju Zhu;Ai-jun Shen;Xin Chen;Canhui Zheng
多发性骨髓瘤（MM）是第二常见的血液恶性肿瘤。几乎所有MM患者最终都会复发，对于复发的难治性MM患者，大多数推荐的治疗方案包括具有不同作用机制的药物组合。因此，临床急需新型药物。Bcl-2抑制剂和HDAC抑制剂的抗mm作用已在临床或临床试验中得到证实，并进一步发现它们之间存在协同作用。本研究设计并合成了一系列Bcl-2/HDAC双靶点抑制剂。其中化合物7e - 7g对HDAC6具有良好的抑制活性，同时对Bcl-2蛋白具有较高的结合亲和力。对人MM细胞株rmi -8226也表现出良好的生长抑制活性，证明了其治疗多发性骨髓瘤的潜在价值。
Multiple myeloma (MM) is the second most common haematological malignancy. Almost all patients with MM eventually relapse, and most recommended treatment protocols for the patients with relapsed refractory MM comprise a combination of drugs with different mechanisms of action. Therefore novel drugs are in urgent need in clinic. Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions. In this study, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized. Among them, compounds7e–7gshowed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They also displayed good growth inhibitory activities against human MM cell line RPMI-8226, which proved their potential value for the treatment of multiple myeloma.