Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening.
Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening.
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DOI：
10.1021/jm501344n
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发表时间：
2015-02
影响因子：
7.3
通讯作者：
Zachary C. Miller;Keun-Sik Kim;Do-Min Lee;V. Kasam;Si Eun Baek;K. Lee;Yan-Yan Zhang-Yan;Lin Ao;K. Carmony;Na-Ra Lee;Shou Zhou;Qingquan Zhao;Yujin Jang;Hyunyoung Jeong;C. Zhan;Wooin Lee;Dong-Eun Kim;K. Kim
中科院分区：
文献类型：
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作者：
Zachary C. Miller;Keun-Sik Kim;Do-Min Lee;V. Kasam;Si Eun Baek;K. Lee;Yan-Yan Zhang-Yan;Lin Ao;K. Carmony;Na-Ra Lee;Shou Zhou;Qingquan Zhao;Yujin Jang;Hyunyoung Jeong;C. Zhan;Wooin Lee;Dong-Eun Kim;K. Kim
我们对蛋白酶体的活性位点进行了340 000个小分子的虚拟筛选，随后进行了体外测定和后续优化，得到了具有吡唑支架的蛋白酶体抑制剂。吡唑-支架化合物显示出优异的代谢稳定性，并且在体内抑制实体肿瘤生长方面是高度有效的。此外，该化合物的有效性未受到硼替佐米或卡非佐米耐药性的负面影响。
We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.