Discovery of Peptide Boronate Derivatives as Histone Deacetylase and Proteasome Dual Inhibitors for Overcoming Bortezomib Resistance of Multiple Myeloma

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).

尽管硼替佐米（bortezomib）等蛋白酶体抑制剂在多发性骨髓瘤（multiple myeloma, MM）的初始治疗中展现出令人满意的临床疗效，但耐药性与复发仍难以避免。近期研究显示，抑制组蛋白去乙酰化酶（HDACs）可恢复硼替佐米耐药型多发性骨髓瘤的药物敏感性。为此，本研究设计了同时靶向HDACs与蛋白酶体的双靶点抑制剂，以解决硼替佐米的耐药难题。其中活性最优的抑制剂ZY-2与ZY-13，对蛋白酶体展现出优异的抑制活性，且对HDACs具有良好的选择性。尤为关键的是，ZY-2不仅对多发性骨髓瘤细胞系RPMI-8226、U266及KM3具备良好的抗增殖活性（半最大抑制浓度IC50分别为6.66、4.31与10.1 nM），同时相较于硼替佐米，其对硼替佐米耐药型多发性骨髓瘤细胞系KM3/BTZ的抗增殖活性更强（IC50分别为8.98 nM与226 nM，P<0.01），且疗效优于HDAC抑制剂MS-275与硼替佐米1:1联合用药组（IC50分别为8.98 nM与98.0 nM，P<0.01）。