205393-21-1Relevant articles and documents
Discovery of a novel dipeptidyl boronic acid proteasome inhibitor for the treatment of multiple myeloma and triple-negative breast cancer
Lei, Meng,Feng, Huayun,Bai, Enhe,Zhou, Hui,Wang, Jia,Qin, Yanru,Zhang, Haoyang,Wang, Xueyuan,Liu, Zhaogang,Hai, Ou,Liu, Jia,Zhu, Yongqiang
supporting information, p. 683 - 691 (2019/01/24)
A series of novel dipeptidyl boronic acid compounds were designed, synthesized and biologically investigated for the inhibition of the β5 subunit of 20S proteasome and several compounds showed high activities with IC50 values of less than 10 nM. Some of these compounds potently inhibited the multiple myeloma (MM) cancer cell lines with IC50 values of less than 10 nM. It was reported that the inhibition of both β2 and β5 subunits strongly increased the cytotoxicity of proteasome inhibitors in solid tumor cells, so some of the compounds were evaluated for the inhibition of the β2 subunit and the solid tumor triple-negative breast cancer cell line MDA-MB-231. The results showed that three compounds were active for both the β2 subunit and the triple-negative breast cancer cell line MDA-MB-231. The in vivo pharmacokinetic results showed that compound 8t had good biological parameters for both ig and iv administrations. An in vivo pharmacodynamic experiment showed that compound 8t inhibited the β5 subunit in whole blood more greatly than the marketed MLN9708 with the same dose at different time periods. A pathological analysis indicated that the injection of compound 8t in the tumor of a triple-negative breast cancer xenograft mice model led to tumor cell necrosis, nucleus condensation, deep staining, cell fragmentation, dissolution and neutrophil infiltration compared with the control group. The data in hand showed that compound 8t might be an effective candidate for the treatment of both MM and triple-negative breast cancer.
Target Validation and Identification of Novel Boronate Inhibitors of the Plasmodium falciparum Proteasome
Xie, Stanley C.,Gillett, David L.,Spillman, Natalie J.,Tsu, Christopher,Luth, Madeline R.,Ottilie, Sabine,Duffy, Sandra,Gould, Alexandra E.,Hales, Paul,Seager, Benjamin A.,Charron, Carlie L.,Bruzzese, Frank,Yang, Xiaofeng,Zhao, Xiansi,Huang, Shih-Chung,Hutton, Craig A.,Burrows, Jeremy N.,Winzeler, Elizabeth A.,Avery, Vicky M.,Dick, Lawrence R.,Tilley, Leann
, p. 10053 - 10066 (2018/11/23)
The Plasmodium proteasome represents a potential antimalarial drug target for compounds with activity against multiple life cycle stages. We screened a library of human proteasome inhibitors (peptidyl boronic acids) and compared activities against purified P. falciparum and human 20S proteasomes. We chose four hits that potently inhibit parasite growth and show a range of selectivities for inhibition of the growth of P. falciparum compared with human cell lines. P. falciparum was selected for resistance in vitro to the clinically used proteasome inhibitor, bortezomib, and whole genome sequencing was applied to identify mutations in the proteasome β5 subunit. Active site profiling revealed inhibitor features that enable retention of potent activity against the bortezomib-resistant line. Substrate profiling reveals P. falciparum 20S proteasome active site preferences that will inform attempts to design more selective inhibitors. This work provides a starting point for the identification of antimalarial drug leads that selectively target the P. falciparum proteasome.
