Discovery of Peptide Boronate Derivatives as Histone Deacetylase and Proteasome Dual Inhibitors for Overcoming Bortezomib Resistance of Multiple Myeloma.,Journal of Medicinal Chemistry

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Discovery of Peptide Boronate Derivatives as Histone Deacetylase and Proteasome Dual Inhibitors for Overcoming Bortezomib Resistance of Multiple Myeloma.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-23 , DOI: 10.1021/acs.jmedchem.9b02161
Yi Zhou ₁ , Xiaoting Liu ₂ , Junxin Xue ₁ , Lulu Liu ₁ , Tao Liang ₁ , Wen Li ₁ , Xinying Yang ₂ , Xuben Hou ₁ , Hao Fang ₁

Affiliation

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).

中文翻译：

发现肽类硼酸盐衍生物作为组蛋白脱乙酰基酶和蛋白酶体双重抑制剂，可克服多发性骨髓瘤的硼替佐米耐药性。

尽管蛋白酶体抑制剂（如硼替佐米）在多发性骨髓瘤（MM）的初始治疗中显示出令人满意的临床益处，但耐药性和复发是不可避免的。最近的研究表明，抑制组蛋白脱乙酰基酶（HDACs）可恢复耐硼替佐米的MM的敏感性。因此，我们设计了针对HDAC和蛋白酶体的双重抑制剂，以解决硼替佐米的耐药性。最有效的抑制剂ZY-2和ZY-13对蛋白酶体表现出优异的抑制作用，并对HDAC具有良好的选择性。特别是ZY-2不仅对MM细胞系RPMI-8226，U266和KM3表现出良好的抗增殖活性（IC50值为6.66、4.31和10.1 nM，

更新日期：2020-04-08

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