Design,synthesis, in vitro and in vivo evaluation,and structure-activity relationship (SAR) discussion of novel dipeptidyl boronic acid proteasome inhibitors as orally available anti-cancer agents for the treatment of multiple myeloma and mechanism studies |
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Authors: | Meng Lei Huayun Feng Enhe Bai Hui Zhou Jia Wang Jingmiao Shi Xueyuan Wang Shihe Hu Zhaogang Liu Yongqiang Zhu |
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Affiliation: | 1. College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, PR China;2. College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, PR China;3. Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., No. 9 Weidi Road, Nanjing 210046, PR China |
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Abstract: | A series of novel dipeptidyl boronic acid inhibitors of 20S proteasome were designed and synthesized. Aliphatic groups at R1 position were designed for the first time to fully understand the SAR (structure–activity relationship). Among the screened compounds, novel inhibitor 5c inhibited the CT-L (chymotrypsin-like) activity with IC50 of 8.21?nM and the MM (multiple myeloma) cells RPMI8226, U266B and ARH77 proliferations with the IC50 of 8.99, 6.75 and 9.10?nM, respectively, which showed similar in vitro activities compared with the compound MLN2238 (biologically active form of marketed MLN9708). To investigate the oral availability, compound 5c was esterified to its prodrug 6a with the enzymatic IC50 of 6.74?nM and RPMI8226, U266B and ARH77 cell proliferations IC50 of 2.59, 4.32 and 3.68?nM, respectively. Furthermore, prodrug 6a exhibited good pharmacokinetic properties with oral bioavailability of 24.9%, similar with MLN9708 (27.8%). Moreover, compound 6a showed good microsomal stabilities and displayed stronger in vivo anticancer efficacy than MLN9708 in the human ARH77 xenograft mouse model. Finally, cell cycle results showed that compound 6a had a significant inhibitory effect on CT-L and inhibited cell cycle progression at the G2M stage. |
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Keywords: | SAR structureactivity relationship UPP ubiquitinproteasome pathway FDA Food and Drug Administration ATP Adenosine triphosphate CP core particle RP regulatory proteasome C-L caspase-like trypsin-like CT-L chymotrypsin-like EDCI 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride HOBt 1-hydroxybenzotriazole DIPEA N,N-diisopropylethylamine half-maximum inhibitory concentration half-life AUC area under the curve SD Sprague-Dawley NMR nuclear magnetic resonance MS mass spectrometry HRMS high resolution mass spectrometry Dipeptidyl boronic acid Proteasome Pharmacokinetic Cell cycle Xenograft mouse model |
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