Design, synthesis and biological evaluation of triaryl compounds as novel 20S proteasome inhibitors

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127508. doi: 10.1016/j.bmcl.2020.127508.

Yajun Yang ¹, Ke Wang ¹, Bo Wu ¹, Ying Yang ¹, Fangfang Lai ², Xiaoguang Chen ², Zhiyan Xiao ³

Affiliations

1 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
2 The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
3 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: xiaoz@imm.ac.cn.

PMID: 32853683 DOI: 10.1016/j.bmcl.2020.127508

Abstract

Thirty novel triaryl compounds were designed and synthesized based on the known Proteasome Inhibitor PI-1840. Most of them showed significant inhibition against the β5c subunit of human 20S Proteasome, and five of them exhibited IC₅₀ values at the sub-micromolar level, which were comparable to or even more potent than PI-1840. The most active two (1c and 1d) showed IC₅₀ values of 0.12 and 0.18 μM against the β5c subunit, respectively, while they displayed no obvious inhibition against the β2c, β1c and β5i subunits. Molecular docking provided informative clues for the subunit selectivity. The potent and subunit selective Proteasome inhibitors identified herein represent new chemical templates for further molecular optimization.

Keywords

Non-covalent; Proteasome inhibitors; Triaryl compounds.

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