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

Yi Zhou; Xiaoting Liu; Junxin Xue; Lulu Liu; Tao Liang; Wen Li; Xinying Yang; Xuben Hou; Hao Fang

doi:10.1021/acs.jmedchem.9b02161

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

J Med Chem. 2020 May 14;63(9):4701-4715. doi: 10.1021/acs.jmedchem.9b02161. Epub 2020 Apr 23.

Authors

Yi Zhou¹, Xiaoting Liu², Junxin Xue¹, Lulu Liu¹, Tao Liang¹, Wen Li¹, Xinying Yang², Xuben Hou¹, Hao Fang¹

Affiliations

¹ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, P.R. China.
² Department of Pharmaceutical Analysis, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, P.R. China.

PMID: 32267687
DOI: 10.1021/acs.jmedchem.9b02161

Abstract

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).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / toxicity
Apoptosis / drug effects
Boronic Acids / chemical synthesis
Boronic Acids / metabolism
Boronic Acids / pharmacology*
Boronic Acids / toxicity
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Discovery
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
G2 Phase Cell Cycle Checkpoints / drug effects
Histone Deacetylase 1 / chemistry
Histone Deacetylase 1 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / metabolism
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylase Inhibitors / toxicity
Humans
Molecular Docking Simulation
Multiple Myeloma / drug therapy
Peptides / chemical synthesis
Peptides / metabolism
Peptides / pharmacology*
Peptides / toxicity
Proteasome Endopeptidase Complex / chemistry
Proteasome Endopeptidase Complex / metabolism
Proteasome Inhibitors / chemical synthesis
Proteasome Inhibitors / metabolism
Proteasome Inhibitors / pharmacology*
Proteasome Inhibitors / toxicity
Protein Binding
Protein Subunits / chemistry
Protein Subunits / metabolism
S Phase Cell Cycle Checkpoints / drug effects

Substances

Antineoplastic Agents
Boronic Acids
Histone Deacetylase Inhibitors
Peptides
Proteasome Inhibitors
Protein Subunits
Proteasome Endopeptidase Complex
HDAC1 protein, human
Histone Deacetylase 1