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1、cancersReviewDrug Development Targeting theUbiquitinProteasome System(UPS)for theTreatment of Human CancersXiaonan Zhang1,2,3,Stig Linder2,4and Martina Bazzaro1,*1Masonic Cancer Center and Department of Obstetrics,Gynecology and Womens Health,University ofMinnesota,Minneapolis,MN 55455,USA;xiaonan.z
2、hangki.se2Department of Oncology-Pathology,Karolinska Institutet,171 77 Stockholm,Sweden;stig.linderliu.se3Department of Immunology,Genetics,and Pathology,Uppsala University,751 05 Uppsala,Sweden4Department of Medical and Health Sciences,Linkping University,SE-58183 Linkping,Sweden*Correspondence:mb
3、azzaroumn.eduReceived:25 February 2020;Accepted:2 April 2020;Published:7 April 2020?Abstract:Cancer cells are characterized by a higher rate of protein turnover and greater demand forprotein homeostasis compared to normal cells.In this scenario,the ubiquitinproteasome system(UPS),which is responsibl
4、e for the degradation of over 80%of cellular proteins within mammaliancells,becomes vital to cancer cells,making the UPS a critical target for the discovery of novelcancer therapeutics.This review systematically categorizes all current reported small moleculeinhibitors of the various essential compo
5、nents of the UPS,including ubiquitin-activating enzymes(E1s),ubiquitin-conjugating enzymes(E2s),ubiquitin ligases(E3s),the 20S proteasome catalytic coreparticle(20S CP)and the 19S proteasome regulatory particles(19S RP),as well as their mechanism/s ofaction and limitations.We also discuss the immuno
6、proteasome which is considered as a prospectivetherapeutic target of the next generation of proteasome inhibitors in cancer therapies.Keywords:ubiquitin;cancer;targeted therapy;chemoresistance1.The UbiquitinProteasome System Is Essential for the Maintenance of Protein HomeostasisIn mammalian cells,p
7、rotein turnover must be strictly regulated as nearly one-third of the newlysynthesized proteins are rapidly degraded with a half-life no more than 10 min 1.At the sametime,proteins that are damaged or misfolded also require prompt degradation to keep a functionalcellular metabolism 2.The ubiquitinpr
8、oteasome system(UPS)is a specialized proteolysis systemthat controls protein degradation and plays an essential role in cellular protein homeostasis 3,4.Evidence has revealed that up to 80%of cellular proteins are degraded through the UPS which speaksabout its importance not only in the regulation o
9、f protein homeostasis,but also in the management ofnumerous cellular regulators relating to DNA damage and repair,cell proliferation and survival,celldifferentiation as well as drug resistance 511.Aseriesofessentialcomponentsubiquitin,ubiquitin-activatingenzymes(E1s),ubiquitin-conjugating enzymes(E2
10、s),ubiquitin ligases(E3s),deubiquitinating enzymes(DUBs),as well as the 26S proteasomeconstitute the UPS 12,13.Ubiquitin is a highly conserved 76 aminoacid proteins that oversees marking to-be-degraded proteins by covalent attachment through anisopeptide bond between the carboxy glycine residue(G76)
11、of ubiquitin to the-amino groups of lysineresidues 14.The 26S proteasome is a large multi-subunit shredder where ubiquitin-tagged proteinsare degraded into smaller peptides which are either further degraded into amino acids or recycled forfurther application during other cellular metabolic processes
12、.For example,Cyclin B1 is degraded byproteasome into multiple short chains to regulate cell cycle 15,16.Oxidized histone protein Htb2,aCancers 2020,12,902;doi:10.3390/ 2020,12,9022 of 34core component of the nucleosome,which is critical for transcription and cell cycle,is recognized andlinked by Lys
13、ine Residue 48(K48)and further degraded by the proteasome 17,18;DbpB(also namedY-box protein 1),a transcription factor,is reported to selectively recognize the Y-box promoter element.Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolyticcleavage by the
14、proteasome complex 19,20;NF-B(nuclear factor kappa-light-chain-enhancer ofactivated B cells)is located outside the nucleus and is reported to be involved in DNA transcriptionas well as cell survival 21,22.The NF-B p105 is the precursor of NF-B p50.It is evident thatNF-B p105 is cleaved and selective
15、ly degraded at the C-terminus by proteasome,generating theactive form of NF-B p50 23.Products of UPS degradation can also be further degraded into singleamino acids by aminopeptidases 24.Aminopeptidases are the class of enzymes that catalyze thefinal steps in the ubiquitinproteasome pathway by break
16、ing down shorter peptides(5 residues)into even smaller fragments 25.Many,but not all,of aminopeptidases,are zinc metalloenzymes,such as leucine aminopeptidases(lAPs)and methionine aminopeptidases(metAPs)26,27.Studiesshowed that blocking the activity of the aminopeptidases by inhibitor of bestatin co
17、uld generate amajor accumulation of peptides which are 25 residues long 28.The 26S proteasome contains one/two 19S regulatory particles(19S RP)which mainly regulatethe translocation of ubiquitinated proteins to the 20S CP and one 20S core particle(20S CP)in whichproteolysis finally occurs 29,30.In g
18、eneral,two main processes are associated with the process ofdegradation of proteins by the UPS:(1)tagging the to-be-degraded proteins by polyubiquitination(normally more than four ubiquitins),and(2)proteolytic degradation of the polyubiquitinated proteinby the 26S proteasome complex 31,32.Each step
19、incorporates an intricate and complex spectrum ofprotein interactions and biochemical reactions(Figure 1).Cancers 2020,12,x 2 of 31 core component of the nucleosome,which is critical for transcription and cell cycle,is recognized and linked by Lysine Residue 48(K48)and further degraded by the protea
20、some 17,18;DbpB(also named Y-box protein 1),a transcription factor,is reported to selectively recognize the Y-box promoter element.Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolytic cleavage by the proteasome complex 19,20;NF-B(nuclear factor kappa-
21、light-chain-enhancer of activated B cells)is located outside the nucleus and is reported to be involved in DNA transcription as well as cell survival 21,22.The NF-B p105 is the precursor of NF-B p50.It is evident that NF-B p105 is cleaved and selectively degraded at the C-terminus by proteasome,gene
22、rating the active form of NF-B p50 23.Products of UPS degradation can also be further degraded into single amino acids by aminopeptidases 24.Aminopeptidases are the class of enzymes that catalyze the final steps in the ubiquitinproteasome pathway by breaking down shorter peptides(1Inhibits the chymo
23、trypsin-likeactivity of the proteasome byreversible binding to the 5subunit thus inhibits proteasomalactivity and leads to accumulationof polyubiquitinated proteins incellsMultiple MyelomaMantle cell lymphomaAcute myeloid leukemialung cancers hepatocellularcarcinomaIntrahepaticCholangiocarcinomaRela
24、psed/RefractoryMultiple MyelomaNeuroblastomaColorectal CancerHead and Neck CancerThyroid CarcinomaMore cases tohttps:/clinicaltrials.govHaemolytic anaemiaImmunethrombocytopeniaLung diseaseCold agglutinindiseaseAmyloidosisMacroglobulinemia98104Carfilzomib5Covalent bonds to proteasomecatalytic subunit
25、s,predominantly5Multiple myelomaRelapsed and/or refractorymultiple myelomaLymphomaChronic lymphocyticleukemiaThyroid cancerRefractory renal cellcarcinomaLung cancerMore cases tohttps:/clinicaltrials.govPulmonary arterialhypertension105112Cancers 2020,12,9029 of 34Table 2.Cont.CompoundsTargetModes of
26、 ActionTargeted CancerTypes in PreclinicalStudiesTargeted Cancer Types inClinical Studies orTherapiesOther DiseaseRef.Inhibitors targeting 20S core particle of the proteasomeIxazomib5 1First orally bioavailableproteasome inhibitor drug,predominantly targeting 5Multiple myelomaRefractory or relapsedm
27、ultiple myelomaAcute myeloid leukemiaRelapsed refractory acutemyeloid leukemiaHodgkin and T-celllymphomaMantle cell lymphomaNon-hematologicmalignancies lymphomaBreast cancerGlioblastomaBladder cancerRenal cell carcinomaWaldenstrommacroglobulinemiaSolitary osseousplasmacytomaMore cases tohttps:/clini
28、caltrials.govAl amyloidosisAutoimmunecytopeniaHIVLupus nephritisKidney diseases113119Oprozomib5 1A structural homologue of CFZ,orally available and applied topatients with relapsed afterreceiving BTZ-and CFZ-basedtherapiesMultiple MyelomaRelapsed and/or refractorymultiple myelomaHepatocellular carci
29、nomaWaldenstrommacroglobulinemiaNon-central nervoussystem malignanciesNo reportedapplications120123Cancers 2020,12,90210 of 34Table 2.Cont.CompoundsTargetModes of ActionTargeted CancerTypes in PreclinicalStudiesTargeted Cancer Types inClinical Studies orTherapiesOther DiseaseRef.Inhibitors targeting
30、 20S core particle of the proteasomeMarizomib5 2 1Irreversibly inhibits the activity ofproteasome and more effectivelyinduces apoptosis in tumor cellsfrom MM and chronic lymphocyticleukemia patients,while shows alower toxicity to normal cells thanBTZMultiple MyelomaRelapsed and/or refractorymultiple
31、 myelomaEpendymomaNon-small Cell LungCancerPancreatic CancerMelanomaLymphomaGlioblastomaNo reportedapplications124128Inhibitors targeting 19S regulatory particle of the proteasomeIU1IU1-47USP14Targets the thiol group in theactive cysteine site in USP14protease and significantly decreasecell prolifer
32、ation,migration,andinvasion.Breast cancerLung cancerNo reportedapplications129,130b-AP15USP14UCHL5Targets both UCHL5 and USP14,disrupts the aggresome formationin cancer cells by activatingcaspase to further induceapoptosis relating to anupregulation of oxidative stressAcute myeloidleukemiaMultiple m
33、yelomaLarge b celllymphomaMantle celllymphomaNeuroblastomaProstate cancerBreast cancerLung cancerHead and neck cancerColon cancerOvarian cancerNo reportedapplications131141Cancers 2020,12,90211 of 34Table 2.Cont.CompoundsTargetModes of ActionTargeted Cancer Typesin Preclinical StudiesTargeted Cancer
34、 Types inClinical Studies orTherapiesOther DiseaseRef.Inhibitors targeting 19S regulatory particle of the proteasomeVLX1570USP14UCHL5An analog of b-AP15,more effectivethan b-AP15 in inhibiting tumorprogressionSee targeted cancer typesof b-AP15Multiple MyelomaNo reportedapplications142145RA-9USP14Rea
35、cts with the sulfurs in the activesite cysteine and inhibitsproteasome-associated DUBsBreast cancer Ovariancancer Cervical cancerRheumatoid arthritis146,147WP1130UCHL5USP14USP9XDirectly inhibits USP9X in additionto UCHL5 and USP14,inducesapoptosis and prevents drugresistance in malignancies throughM
36、cl-1 degradationAcute myeloid leukemiaChronic myelogenousleukemiaHuman mesotheliomaLung cancerColon cancer ProstatecancerHepatocellular carcinomaNo reportedapplications148154OPARPN11A zinc ion chelator,inhibits theactivity of RPN11 metal-containingenzymes of 19S and inducesapoptosis including cell l
37、ines whichare BTZ resistantMultiple myelomaHepatocellular carcinomaCervical cancer BreastcarcinomaSarcoidosis1551618TQRPN11A strong RPN11-specific inhibitionof proteasome 19S subunit and is apotent apoptosis inducer in MM cellsLung carcinomaColon cancerNo reportedapplications162ThiolutinRPN11The red
38、uced form of Thiolutin is aninhibitor of JAB1/MPN/Mov34(JAMM)domain-containingmetalloprotease RPN11 by chelatingZn2+-ions which is specifically toxicto cancer cells by hampering proteinturnoverOnly in cell free systemNo reportedapplications163Cancers 2020,12,90212 of 34Table 3.Inhibitors of immunopr
39、oteasome complex.CompoundsTargetModes of ActionTargeted CancerTypes in PreclinicalStudiesTargeted CancerTypes in ClinicalStudies or TherapiesOther DiseaseRef.ONX-09145iThe first epoxyketone-based peptidylimmunoproteasome selective inhibitor towards5iRheumatoid arthritis(mouse model)164,165PR-9245iAn
40、 epoxyketone-based peptidyl selectiveinhibitor of 5i immunoproteasome,displays amuch stronger inhibitory activity(5c/5i=91)and blocks the growth of multiple myelomain vitro and in vivo.Multiple myeloma166,167KZR-6165i,2i and 1iThe only epoxyketone-based peptidylimmunoproteasome selective inhibitor t
41、ested inclinic so farSystemic lupuserythematosus(NCT03393013)168Cancers 2020,12,90213 of 343.2.Ubiquitin-Conjugating Enzymes(E2s)InhibitorsE2 enzymes,which act as intermediates between the E1 and E3 proteins,determine the type ofthe polyubiquitin chain linkage.However,each E2 needs to associate and
42、cooperate with a specific setof E3s;the more applicable approach is to block the E2E3 association through the inhibition of E3s.Thus,E2 enzymes have received far less attention as drug targets in discovering novel proteasomeinhibitors.Among the few compounds developed,CC0651an allosteric inhibitor o
43、f human E2enzyme hCdc34causes large-scale structural rearrangements that affect the discharge of ubiquitinacceptor lysine residues 169.NSC697923 is another inhibitor targeting the Ubc13Uev1A E2 enzymeand blocks the formation of the E2Ub thioester conjugate,further inhibiting the activation of NF-Bsi
44、gnaling,leading to the reduced proliferation and viability of cancer cells 170.Please see Table 1.3.3.Ubiquitin Ligases(E3s)InhibitorsSofar,morethansixhundredE3enzymeshavebeendiscoveredandfoundtodiverselyregulatetheactivity of downstream substrates 171.E3 ligases are closely and specifically related
45、 to fundamentalcellular processes in human cancers by regulating the degradation of tumor promoters or suppressors,thus inhibiting the activity of tumor-related E3 ligases could enhance the efficiency of cancer therapy byminimizing off-target side effects.More importantly,unlike E1 or E2,E3 ligases
46、exhibit high specificityto a certain substrate.In this scenario,the targeting of E3 can be achieved in several ways,includingthrough the inhibition of its expression levels,altering of its subcellular localization and via preventingits proper assembly 13,40 and/or interaction with cellular substrate
47、s 172,173.The current mainapproach for the development of anti-E3-based therapies is via small-molecule screening technologies.As such,a number of studies have identified compounds targeting different E3 ligases and furtherimpact the function and activity of UPS.The most studied E3 ligase is MDM2,wh
48、ich negatively regulates p53 and is important forcell survival 174176,losing Mdm2 is reported to induce cell death bothin vitroandin vivoin ap53-dependent manner 177.Nutlin-3a,the first molecule described targeting MDM2,inhibits theinteraction between Mdm2 and p53 178,eventually arrests cell cycle,i
49、nhibits growth of cancer cells,and induces cell deathin vitroandin vivo.The derivatives of nutlin-3a,such as(R05503781)179and RG7112(R05045337)180,have exhibited greater activitiesin vitro;however,the first resultreport of RG7112 in clinical trials for the treatment of liposarcoma is not so encourag
50、ing,due tothe reason that even the expression levels of p53 and p21 increased in response to the treatment ofRG7112,out of twenty patients,only one(1/20)showed a partial response.Furthermore,even thoughit specifically inhibits the activity of MDM2,RG7112 still shows relatively severe side effects in