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).