Research progress on selective immunoproteasome inhibitors

doi:10.3785/j.issn.1008-9292.2019.12.15

J Zhejiang Univ (Med Sci)

2019, Vol. 48

Issue (6): 688-694 DOI: 10.3785/j.issn.1008-9292.2019.12.15

Research progress on selective immunoproteasome inhibitors

KONG Limin¹(

),LU Jingyi²,ZHU Huajian²,ZHANG Jiankang^2,*(

)

1. Department of Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
2. School of Medicine, Zhejiang University City College, Hangzhou 310015, China

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Abstract

Immunoproteasome is associated with various diseases such as hematologic malignancies, inflammatory, autoimmune and central nervous system diseases, and over expression of immunoproteasome is observed in all of these diseases. Immunoproteasome inhibitors can reduce the expression of immunoproteasome by inhibiting the production of related cell-inducing factors and the activity of T lymphocyte for treating related diseases. In order to achieve good efficacy and reduce the toxic effects, key for development of selective immunoproteasome inhibitors is the high selectivity and potent activity of the three active subunits of the proteasome. This review summarizes the structure and functions of immunoproteasome and the associated diseases. Besides, structure, activity and status of selective immunoproteasome inhibitors are also been highlighted.

Key words： Proteasomeinhibitors/analysis Multienzyme complexes Structure-activity relationship Autoimmune diseases Proteasome inhibitors/therapy Bortezomib Review

Received: 30 January 2019 Published: 19 January 2020

CLC:	R94
	R967

Corresponding Authors: ZHANG Jiankang E-mail: liminkong@zju.edu.cn;zhang_jk@zucc.edu.cn

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	KONG Limin
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Cite this article:

KONG Limin,LU Jingyi,ZHU Huajian,ZHANG Jiankang. Research progress on selective immunoproteasome inhibitors. J Zhejiang Univ (Med Sci), 2019, 48(6): 688-694.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2019.12.15 OR http://www.zjujournals.com/med/Y2019/V48/I6/688

选择性免疫蛋白酶体抑制剂研究进展

免疫蛋白酶体与血液肿瘤、感染性疾病、自身免疫性疾病、中枢神经系统疾病等密切相关，这些疾病均呈现免疫蛋白酶体高表达。免疫蛋白酶体抑制剂可通过抑制相关细胞诱导因子的生成和自身反应性T细胞的活性来阻断免疫蛋白酶体的表达，从而治疗相关疾病。选择性免疫蛋白酶体抑制剂研发的关键是针对免疫型蛋白酶体的高度选择性，兼顾蛋白酶体上三个活性亚基的活性水平，才能在达到良好疗效的同时减少不良反应。本文介绍了免疫蛋白酶体的结构、功能，以及与多种疾病之间的关系，针对目前已报道的环氧酮肽类共价结合、其他短肽类共价结合、短肽类非共价结合选择性免疫蛋白酶体抑制剂的结构、活性及发展现状作一综述。

关键词： 半胱氨酸内肽酶类/分析, 多酶复合物, 构效关系, 自身免疫疾病, 蛋白酶体抑制剂/治疗, 硼替佐米, 综述

Fig 1 Structures of selective epoxyketone peptidyl immunoproteasome inhibitors

Tab 1 Proteasome inhibitory activities and selectivities of KZR-504 and its derivatives^[15]

(μmol/L)

Fig 2 Binding modes of ONX-0914 with immunoproteasome and constitutive proteasome

Tab 2 Proteasome inhibitory activities and selectivities of ONX-0914 and its derivatives^{[12, 18]}

(nmol/L)

Fig 3 Structures of other peptidyl covalent selective immunoproteasome inhibitors

Tab 3 Proteasome inhibitory activities and selectivities of sulfonyl fluoride and corresponding epoxyketone derivatives^[27]

(μmol/L)

Fig 4 Structures of non-covalent peptidyl selective immunoproteasome inhibitors


[1]	ZHANG J , WU P , HU Y . Clinical and marketed proteasome inhibitors for cancer treatment[J]. Curr Med Chem, 2013, 20 (20): 2537- 2551 doi: 10.2174/09298673113209990122

[2]	CIECHANOVER A . The ubiquitin-proteasome pathway:on protein death and cell life[J]. EMBO J, 1998, 17 (24): 7151- 7160 doi: 10.1093/emboj/17.24.7151

[3]	SOAVE C L , GUERIN T , LIU J et al. Targeting the ubiquitin-proteasome system for cancer treatment:discovering novel inhibitors from nature and drug repurposing[J]. Cancer Metastasis Rev, 2017, 36 (4): 717- 736 doi: 10.1007/s10555-017-9705-x

[4]	MEINERS S , EVANKOVICH J , MALLAMPALLI R K . The ubiquitin proteasome system as a potential therapeutic target for systemic sclerosis[J]. Transl Res, 2018, 198 17- 28 doi: 10.1016/j.trsl.2018.03.003

[5]	CROMM P M , CREWS C M . The proteasome in modern drug discovery:second life of a highly valuable drug target[J]. ACS Cent Sci, 2017, 3 (8): 830- 838 doi: 10.1021/acscentsci.7b00252

[6]	VERBRUGGE S E , SCHEPER R J , LEMS W F et al. Proteasome inhibitors as experimental therapeutics of autoimmune diseases[J]. Arthritis Res Ther, 2015, 17 17 doi: 10.1186/s13075-015-0529-1

[7]	ZHENG Q , HUANG T , ZHANG L et al. Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases[J]. Front Aging Neurosci, 2016, 8 303

[8]	LIP P Z , DEMASI M , BONATTO D . The role of the ubiquitin proteasome system in the memory process[J]. Neurochem Int, 2017, 102 57- 65 doi: 10.1016/j.neuint.2016.11.013

[9]	VISEKRUNA A , SLAVOVA N , DULLAT S et al. Expression of catalytic proteasome subunits in the gut of patients with Crohn's disease[J]. Int J Colorectal Dis, 2009, 24 (10): 1133- 1139 doi: 10.1007/s00384-009-0679-1

[10]	BASLER M , DAJEE M , MOLL C et al. Prevention of experimental colitis by a selective inhibitor of the immunoproteasome[J]. J Immunol, 2010, 185 (1): 634- 641 doi: 10.4049/jimmunol.0903182

[11]	OH I S, TEXTORIS-TAUBE K, SUNG P S, et al. Immunoproteasome induction is suppressed in hepatitis C virus-infected cells in a protein kinase R-dependent manner[J/OL]. Exp Mol Med, 2016, 48(11): e270.

[12]	HUBER E M , BASLER M , SCHWAB R et al. Immuno-and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity[J]. Cell, 2012, 148 (4): 727- 738 doi: 10.1016/j.cell.2011.12.030

[13]	GUIMAR?ES G , GOMES M , CAMPOS P C et al. Immunoproteasome subunits are required for CD8+ T Cell function and host resistance to brucella abortus infection in mice[J]. Infect Immun, 2018, 86 (3):

[14]	JOHNSON H , LOWE E , ANDERL J L et al. Required immunoproteasome subunit inhibition profile for anti-inflammatory efficacy and clinical candidate KZR-616((2 S, 3 R)-N-((S)-3-(Cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propenamide)[J]. J Med Chem, 2018, 61 (24): 11127- 11143 doi: 10.1021/acs.jmedchem.8b01201

[15]	JOHNSON H , ANDERL J L , BRADLEY E K et al. Discovery of highly selective inhibitors of the immunoproteasome low molecular mass polypeptide 2(LMP2) subunit[J]. ACS Med Chem Lett, 2017, 8 (4): 413- 417 doi: 10.1021/acsmedchemlett.6b00496

[16]	HO Y K , BARGAGNA-MOHAN P , WEHENKEL M et al. LMP2-specific inhibitors:chemical genetic tools for proteasome biology[J]. Chem Biol, 2007, 14 (4): 419- 430 doi: 10.1016/j.chembiol.2007.03.008

[17]	MUCHAMUEL T , BASLER M , AUJAY M A et al. A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis[J]. Nat Med, 2009, 15 (7): 781- 787 doi: 10.1038/nm.1978

[18]	DE BRUIN G , HUBER E M , XIN B T et al. Structure-based design of β1i or β5i specific inhibitors of human immunoproteasomes[J]. J Med Chem, 2014, 57 (14): 6197- 6209 doi: 10.1021/jm500716s

[19]	MYUNG J , KIM K B , LINDSTEN K et al. Lack of proteasome active site allostery as revealed by subunit-specific inhibitors[J]. Mol Cell, 2001, 7 (2): 411- 420 doi: 10.1016/S1097-2765(01)00188-5

[20]	BASLER M , LAUER C , MOEBIUS J et al. Why the structure but not the activity of the immunoproteasome subunit low molecular mass polypeptide 2 rescues antigen presentation[J]. J Immunol, 2012, 189 (4): 1868- 1877 doi: 10.4049/jimmunol.1103592

[21]	KUHN D J , HUNSUCKER S A , CHEN Q et al. Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors[J]. Blood, 2009, 113 (19): 4667- 4676 doi: 10.1182/blood-2008-07-171637

[22]	DUBIELLA C , CUI H , GERSCH M et al. Selective inhibition of the immunoproteasome by ligand-induced crosslinking of the active site[J]. Angew Chem Int Ed Engl, 2014, 53 (44): 11969- 11973 doi: 10.1002/anie.201406964

[23]	DUBIELLA C , BAUR R , CUI H et al. Selective inhibition of the immunoproteasome by structure-based targeting of a non-catalytic cysteine[J]. Angew Chem Int Ed Engl, 2015, 54 (52): 15888- 15891 doi: 10.1002/anie.201506631

[24]	SINGH P K , FAN H , JIANG X et al. Immunoproteasome β5i-selective dipeptidomimetic inhibitors[J]. Chem Med Chem, 2016, 11 (19): 2127- 2131 doi: 10.1002/cmdc.201600384

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