蛋白质降解靶向嵌合体的研究进展

余赛红, 王孝举, 郑晓亮, 于洁

中国药学杂志 ›› 2021, Vol. 56 ›› Issue (11) : 861-867.

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中国药学杂志 ›› 2021, Vol. 56 ›› Issue (11) : 861-867. DOI: 10.11669/cpj.2021.11.001
综述

蛋白质降解靶向嵌合体的研究进展

  • 余赛红, 王孝举, 郑晓亮, 于洁*
作者信息 +

Advances in Proteolysis Targeting Chimeras

  • YU Sai-hong, WANG Xiao-ju, ZHENG Xiao-liang, YU Jie*
Author information +
文章历史 +

摘要

近年来,蛋白质降解靶向嵌合体(proteolysis targeting chimeras,PROTACs)作为一种新型靶向治疗方式成为人们关注的焦点。PROTACs是一类双靶点嵌合体分子,由3个部分组成:靶向结合目标蛋白的配体、招募E3泛素连接酶的配体以及两者之间的连接链。它能将目标蛋白与E3泛素连接酶的距离拉近,利用细胞内固有的泛素-蛋白酶体系统选择性诱导目标蛋白降解。与传统的小分子抑制剂相比,PROTACs在药物的剂量、选择性、耐药性以及调节“不可成药靶点”等方面具有潜在优势,目前已开始从基础研究走向临床试验。笔者将结合最新的相关研究进展,总结PROTACs的优势、设计要素以及目前面临的主要问题等。

Abstract

In recent years, proteolysis targeting chimeras (PROTACs) have emerged as a novel therapeutic modality in drug discovery and become the focus of great interest. PROTACs are bifunctional molecules consisting of a ligand targeting a POI (protein of interest), a ligand for recruiting an E3 ubiquitin ligase and a linker connecting these ligands. PROTACs are designed to bind both the target protein and the E3-ubiquitin ligase, therefore recruiting an E3 ubiquitin ligase to a specific target protein and thereby providing a mechanism to ubiquitinate and degrade specific pathological proteins by the proteasome. Compared with traditional small-molecule inhibitors, PROTACs have the potential advantages with respect to dosage, selectivity, drug resistance and modulating "undruggable" targets. Based on the latest research progress, this review summarizes the advantages of PROTACs, the elements of PROTACs design, and the current problems.

关键词

蛋白质降解靶向嵌合体 / 蛋白质降解 / 靶向治疗 / 泛素-蛋白酶体系统

Key words

proteolysis targeting chimeras / protein degradation / targeted therapy / ubiquitin-proteasome system

引用本文

导出引用
余赛红, 王孝举, 郑晓亮, 于洁. 蛋白质降解靶向嵌合体的研究进展[J]. 中国药学杂志, 2021, 56(11): 861-867 https://doi.org/10.11669/cpj.2021.11.001
YU Sai-hong, WANG Xiao-ju, ZHENG Xiao-liang, YU Jie. Advances in Proteolysis Targeting Chimeras[J]. Chinese Pharmaceutical Journal, 2021, 56(11): 861-867 https://doi.org/10.11669/cpj.2021.11.001
中图分类号: R965   

参考文献

[1] FERLAY J, SOERJOMATARAM I, DIKSHIT R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012[J]. Int J Cancer, 2015,136(5):359-386.
[2] SAKAMOTO K M, KIM K B, KUMAGAI A, et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation[J]. Proc Natl Acad Sci USA, 2001, 98(15):8554-8559.
[3] VEGGIANI G, GERPE M C R, SIDHU S S, et al. Emerging drug development technologies targeting ubiquitination for cancer therapeutics[J]. Pharmacol Ther, 2019, 199:139-154.
[4] SCHAPIRA M, CALABRESE M F, BULLOCK A N, et al. Targeted protein degradation: expanding the toolbox[J]. Nat Rev Drug Discov, 2019, 18(12):949-963.
[5] DANG C V, REDDY E P, SHOKAT K M, et al. Drugging the “undruggable” cancer targets[J]. Nat Rev Cancer, 2017, 17(8):502-508.
[6] ZHOU H, BAI L, XU R, et al. Structure-Based Discovery of SD-36 as a potent, selective, and efficacious PROTAC degrader of STAT3 protein[J]. J Med Chem, 2019,62(24):11280-11300.
[7] CHESSUM N E A, SHARP S Y, CALDWELL J J, et al. Demonstrating in-cell target engagement using a pirin protein degradation probe (CCT367766)[J]. J Med Chem, 2018, 61(3):918-933.
[8] BASSI Z I, FILLMORE M C, MIAH A H, et al. Modulating PCAF/GCN5 immune cell function through a PROTAC approach[J]. ACS Chem Biol, 2018, 13(10):2862-2867.
[9] BONDESON D P, SMITH B E, BURSLEM G M, et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead[J]. Cell Chem Biol, 2018, 25(1):1-15.
[10] HUANG H T, DOBROVOLSKY D, PAULK J, et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader[J]. Cell Chem Biol, 2018, 25(1):1-12.
[11] BUHIMSCHI A D, ARMSTRONG H A, TOURE M, et al. Targeting the C481S Ibrutinib-resistance mutation in Bruton′s tyrosine kinase using PROTAC-mediated degradation[J]. Biochemistry, 2018, 57(26):3564-3575.
[12] SUN Y, ZHAO X, DING N, et al. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies[J]. Cell Res, 2018, 28(7):779-781.
[13] PETTERSSON M, CREWS C M. PROteolysis targeting chimeras (PROTACs)-past, present and future[J]. Drug Discov Today Technol, 2019, 31:15-27.
[14] SUN X, WANG J, YAO X, et al. A chemical approach for global protein knockdown from mice to non-human primates[J]. Cell Discov, 2019, 5(10):1-13.
[15] LI Y, YANG J, AGUILAR A, et al. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression[J]. J Med Chem, 2019, 62(2):448-466.
[16] LU M, LIU T, JIAO Q, et al. Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway[J]. Eur J Med Chem, 2018, 146:251-259.
[17] SILVA M C, FERGUSON F M, CAI Q, et al. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models[J]. Elife, 2019, 8:e45457.
[18] SCHNEEKLOTH J S J R, FONSECA F N, KOLDOBSKIY M, et al. Chemical genetic control of protein levels: selective in vivo targeted degradation[J]. J Am Chem Soc, 2004, 126(12):3748-3754.
[19] LEE H, PUPPALA D, CHOI E Y, et al. Targeted degradation of the aryl hydrocarbon receptor by the PROTAC approach: a useful chemical genetic tool[J]. Chembiochem, 2007, 8(17):2058-2062.
[20] SCHNEEKLOTH A R, PUCHEAULT M, TAE H S, et al. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics[J]. Bioorg Med Chem Lett, 2008, 18(22):5904-5908.
[21] SEKINE K, TAKUBO K, KIKUCHI R, et al. Small molecules destabilize cIAP1 by activating auto-ubiquitylation[J]. J Biol Chem, 2008, 283(14):8961-8968.
[22] ITOH Y, ISHIKAWA M, NAITO M, et al. Protein knockdown using methyl bestatin-ligand hybrid molecules: design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins[J]. J Am Chem Soc, 2010, 132(16):5820-5826.
[23] BUCKLEY D L, GUSTAFSON J L, VAN MOLLE I, et al. Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1alpha[J]. Angew Chem Int Ed Engl, 2012, 51(46):11463-11467.
[24] SOARES P, GADD M S, FROST J, et al. Group-based optimization of potent and cell-active inhibitors of the von hippel-lindau (VHL) E3 ubiquitin ligase: structure-activity relationships leading to the chemical probe (2S,4R)-1-((S)-2-(1-cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298)[J]. J Med Chem, 2018, 61(2):599-618.
[25] FISCHER E S, BOHM K, LYDEARD J R, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide[J]. Nature, 2014, 512(7512):49-53.
[26] LAI A C, TOURE M, HELLERSCHMIED D, et al. Modular PROTAC design for the degradation of oncogenic BCR-ABL[J]. Angew Chem Int Ed Engl, 2016, 55(2):807-810.
[27] CHAN K H, ZENGERLE M, TESTA A, et al. Impact of target warhead and linkage vector on inducing protein degradation: comparison of bromodomain and extra-terminal (BET) degraders derived from triazolodiazepine (JQ1) and tetrahydroquinoline (I-BET726) BET inhibitor scaffolds[J]. J Med Chem, 2018, 61(2):504-513.
[28] HAN X, WANG C, QIN C, et al. Discovery of ARD-69 as a highly potent proteolysis targeting chimera (PROTAC) degrader of androgen receptor (AR) for the treatment of prostate cancer[J]. J Med Chem, 2019,62(2):941-964.
[29] GECHIJIAN L N, BUCKLEY D L, LAWLOR M A, et al. Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands[J]. Nat Chem Biol, 2018, 14(4):405-412.
[30] BONDESON D P, MARES A, SMITH I E, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs[J]. Nat Chem Biol, 2015, 11(8):611-617.
[31] BURSLEM G M, SMITH B E, LAI A C, et al. The advantages of targeted protein degradation over inhibition: an RTK case study[J]. Cell Chem Biol, 2018, 25(1):67-77.
[32] CROMM P M, SAMARASINGHE K T G, HINES J, et al. Addressing kinase-independent functions of fak via PROTAC-mediated degradation[J]. J Am Chem Soc, 2018, 140(49):17019-17026.
[33] BURSLEM G M, SONG J, CHEN X, et al. Enhancing antiproliferative activity and selectivity of a FLT-3 inhibitor by proteolysis targeting chimera conversion[J]. J Am Chem Soc, 2018, 140(48):16428-16432.
[34] NUNES J, MCGONAGLE G A, EDEN J, et al. Targeting IRAK4 for degradation with PROTACs[J]. ACS Med Chem Lett, 2019, 10(7):1081-1085.
[35] TOVELL H, TESTA A, ZHOU H, et al. Design and characterization of SGK3-PROTAC1, an isoform specific SGK3 kinase PROTAC degrader[J]. ACS Chem Biol, 2019,14(9):2024-2034.
[36] WANG X, FENG S, FAN J, et al. New strategy for renal fibrosis: targeting Smad3 proteins for ubiquitination and degradation[J]. Biochem Pharmacol, 2016, 116:200-209.
[37] CREW A P, RAINA K, DONG H, et al. Identification and characterization of von hippel-lindau-recruiting proteolysis targeting chimeras (PROTACs) of tank-binding kinase 1[J]. J Med Chem, 2018, 61(2):583-598.
[38] BURSLEM G M, SCHULTZ A R, BONDESON D P, et al. Targeting BCR-ABL1 in chronic myeloid leukemia by PROTAC-mediated targeted protein degradation[J]. Cancer Res, 2019, 79(18):4744-4753.
[39] FARNABY W, KOEGL M, ROY M J, et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design[J]. Nat Chem Biol, 2019, 15(7):672-680.
[40] NOWAK R P, DEANGELO S L, BUCKLEY D, et al. Plasticity in binding confers selectivity in ligand-induced protein degradation[J]. Nat Chem Biol, 2018, 14(7):706-714.
[41] REMILLARD D, BUCKLEY D L, PAULK J, et al. Degradation of the BAF complex factor BRD9 by heterobifunctional ligands[J]. Angewandte Chem, 2017, 56(21):5738-5743.
[42] SCHIEDEL M, HERP D, HAMMELMANN S, et al. Chemically induced degradation of sirtuin 2 (sirt2) by a proteolysis targeting chimera (PROTAC) based on sirtuin rearranging ligands (SirReals)[J]. J Med Chem, 2018, 61(2):482-491.
[43] YANG K, SONG Y, XIE H, et al. Development of the first small molecule histone deacetylase 6 (HDAC6) degraders[J]. Bioorg Med Chem Lett, 2018, 28(14):2493-2497.
[44] LI W, GAO C, ZHAO L, et al. Phthalimide conjugations for the degradation of oncogenic PI3K[J]. Eur J Med Chem, 2018, 151:237-247.
[45] MCCOULL W, CHEUNG T, ANDERSON E, et al. Development of a novel B-cell lymphoma 6 (BCL6) PROTAC to provide insight into small molecule targeting of BCL6[J]. ACS Chem Biol, 2018, 13(11):3131-3141.
[46] BIAN J, REN J, LI Y, et al. Discovery of wogonin-based PROTACs against CDK9 and capable of achieving antitumor activity[J]. Bioorg Chem, 2018, 81:373-381.
[47] WINTER G E, BUCKLEY D L, PAULK J, et al. Phthalimide conjugation as a strategy for in vivo target protein degradation[J]. Science, 2015, 348(6241):1376-1381.
[48] CIEŚLAK M, KAŹMIERCZAK-BARAŃSKA J, KRÓóLEWSKA-GOLIŃSKA K, et al. New thalidomide-resembling dicarboximides target ABC50 protein and show antileukemic and immunomodulatory activities[J]. Biomolecules, 2019, 9(9):446.
[49] SONG Y, PARK P M C, WU L, et al. Development and preclinical validation of a novel covalent ubiquitin receptor Rpn13 degrader in multiple myeloma[J]. Leukemia, 2019, 33(11):2685-2694.
[50] OHOKA N, NAGAI K, HATTORI T, et al. Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin-proteasome pathway[J]. Cell Death Dis, 2014, 5(11):e1513.
[51] OKUHIRA K, OHOKA N, SAI K, et al. Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein[J]. FEBS Lett, 2011, 585(8):1147-1152.
[52] ITOH Y, KITAGUCHI R, ISHIKAWA M, et al. Design, synthesis and biological evaluation of nuclear receptor-degradation inducers[J]. Bioorg Med Chem, 2011, 19(22):6768-6778.
[53] ZHAO Q, LAN T, SU S, et al. Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule[J]. Chem Commun (Camb), 2019, 55(3):369-372.
[54] SAKAMOTO K M, KIM K B, VERMA R, et al. Development of protacs to target cancer-promoting proteins for ubiquitination and degradation[J]. Mol Cell Proteomics, 2003, 2(12):1350-1358.
[55] WARD C C, KLEINMAN J I, BRITTAIN S M, et al. Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications[J]. ACS Chem Biol, 2019, 14(11):2430-2440.
[56] SPRADLIN J N, HU X, WARD C C, et al. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation[J]. Nat Chem Biol, 2019, 15(7):747-755.
[57] ZHANG X, CROWLEY V M, WUCHERPFENNIG T G, et al. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16[J]. Nat Chem Biol, 2019, 15(7):737-746.
[58] SCHEEPSTRA M, HEKKING K F W, VAN HIJFTE L, et al. Bivalent ligands for protein degradation in drug discovery[J]. Comput Struct Biotechnol J, 2019, 17:160-176.
[59] MANIACI C, HUGHES S J, TESTA A, et al. Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation[J]. Nature Commun, 2017, 8(1):830.
[60] TOMOSHIGE S, HASHIMOTO Y, ISHIKAWA M. Efficient protein knockdown of HaloTag-fused proteins using hybrid molecules consisting of IAP antagonist and HaloTag ligand[J]. Bioorg Med Chem, 2016, 24(14):3144-3148.
[61] TINWORTH C P, LITHGOW H, DITTUS L, et al. PROTAC-mediated degradation of Bruton′s tyrosine kinase is inhibited by covalent binding[J]. ACS Chem Biol, 2019, 14(3):342-347.
[62] CYRUS K, WEHENKEL M, CHOI E Y, et al. Impact of linker length on the activity of PROTACs[J]. Mol Biosyst, 2011, 7(2):359-364.
[63] CYRUS K, WEHENKEL M, CHOI E Y, et al. Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs[J]. Chem Med Chem, 2010, 5(7):979-985.
[64] GADD M S, TESTA A, LUCAS X, et al. Structural basis of PROTAC cooperative recognition for selective protein degradation[J]. Nat Chem Biol, 2017, 13(5):514-521.
[65] RICHING K M, MAHAN S, CORONA C R, et al. Quantitative live-cell kinetic degradation and mechanistic profiling of PROTAC mode of action[J]. ACS Chem Biol, 2018, 13(9):2758-2770.
[66] XIA L, LIU W, SONG Y, et al. The present and future of novel protein degradation technology[J]. Curr Top Med Chem, 2019, 19(20):1784-1788.
[67] ZHANG L, RILEY-GILLIS B, VIJAY P, et al. Acquired resistance to bet-PROTACs (proteolysis-targeting chimeras) caused by genomic alterations in core components of E3 ligase complexes[J]. Mol Cancer Ther, 2019, 18(7):1302-1311.
[68] DOBROVOLSKY D, WANG E S, MORROW S, et al. Bruton tyrosine kinase degradation as a therapeutic strategy for cancer[J]. Blood, 2019, 133(9):952-961.

基金

国家自然科学基金面上项目资助(81773626);浙江省医药卫生科技计划项目资助(2020KY104);浙江省医学科学院科技计划项目资助(2019D001)
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