Inducing Targeted Protein Degradation: From Chemical Biology to Drug Discovery and Clinical Applications PDF
Preview Inducing Targeted Protein Degradation: From Chemical Biology to Drug Discovery and Clinical Applications
D ow nloaded from https://onlinelibrary.w iley.com /doi/ by ibrahim ragab - C IDnedgurcaidnagt Tioanrgeted Protein ochrane Germ any , W iley O nline L ibrary on [22/12/2022]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense D ow nloaded from https://onlinelibrary.w iley.com /doi/ by ibrahim ragab - C Inducing Targeted Protein ochrane G erm Degradation any , W iley O nline L FArpopmli cCahtieomnsical Biology to Drug Discovery and Clinical ibrary on [22/12/2022]. See the T Edited by Philipp Cromm erms and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense D ow nloaded from https://onlinelibrary.w iley.com /doi/ by ibrahim ragab - C ochrane G Editor All books published by WILEY-VCH are carefully erm DBra. yPehri lAipGp Cromm ppcoruonbdtlaiusichneeedrd. diNnoe tnvhoeerts tweh eablroerosaskn,s ta, tuihntehc loiunrdsfo,i nremgd itathotiiross n,b aonodk , any , Wiley O Research & Development, Pharmaceuticals to be free of errors. Readers are advised to keep nline L M13u3e4l2l eBrestrrlainss, eG 1e7rm8any ipiLBAnnirr b aiocmtrdaciasetvirhandey l drLuooti rgfetb ahunCrlaaoet dlrt nyyr esge tCbtrcaaeaeoitts leriassndm l oCo afreagco nrcuordut ittn shrNh,ga eiod-tsri.ea :nbi .tta-aoePp,om upikbllsl ilu ieimscsd aata rtfvyaioao triniloa Dnbasle,t a ibrary on [22/12/2022]. See the T fBDTlNddiranisheoabttubemtslaiit. o odDts ahtcng-rheh nireauseaeb l a ptb p.BNsdvhiucbraaeihbiclit>til lieiioaoi.sn cbNgnhfarloa ateaLlrit bfmoioiibionenbarn; lt a itiidanohroley tnbetth.h iaIpebeinkull eitDboedltrei hsnbuheietbekstdl c aih otb egy< r tahhptethp i:c/ / erms and Conditions (https://onlinelibrary.w © 2023 Wiley‐VCH GmbH, Boschstr. 12, iley.com 69469 Weinheim, Germany /term Attpnlarhhoalnilrons g r ttsbuiorlgoaaaphongtritkeisosn m nwmrtie iiintastntgheyetr, ood bvmu eeoot ditrr chw etr(epriornrairf tnoicltlaldesmunlnuadg, c tpiuoeeneraddgr g a m iietnnnhsiyt s)oao .sosn iNaetoyh omn ofe o fprfa rr acmmorhmte i –noa tfnebh sye – s-and-conditions) on Wiley O publishers. Registered names, trademarks, etc. nline L PeumuPrsniaeDnprdtFrk o IieISntSdeB B tcaNhNtse:i: s ds u bb99co7yh7o 88,lk ‐a‐a3,w3 r‐e‐e5.5v 2n2e7n7o‐‐ t3w3 t55oh00 e1b1n3e7‐ ‐nc19oont ssipdeecriefdic ally ibrary for rules of use; OA MeoCTyPoBpavuoenebosrn k IeD ShtIBSteeiBNsinmiNg:g :n, G:9 S7e9tr87rFma‐8O3i‐va‐3R5en‐M,25y C72G‐7h8‐Ee38Bn63nE2612aR‐0i,5,‐ I8ndia articles are governed by the applicable C reative C om m ons L icense D ow nloaded from v https://onlinelibrary.w iley.com /doi/ by ibrahim ragab - C Contents ochrane G erm any , W iley O Preface xiii nline L 1111... 112 . 1 TD IWDnaaethrnvrgaoieeetdl ltoC ueHpdacm. tn OPi oeBr nnDoet to t eEoonif xonT pvT aDaearncergg,tg eeLetrdaetae uddfdrr aPao Pt rmiMrooo t.n tetLh ei–uniin shT D BhDaeoenego dgSrk ratP?aodh draiyalti2 itpSoioponn MF(:T a.C rPCh rDoro)1m nmo1logy and ibrary on [22/12/2022]. See the Term 111...222...132 MMMMBPBeiiiiiiooplllllleeeetooissssdggttttoooooyynnnn mToeeeeofi s m123oF :::lu esTEI3 tlmvihacerep6 slV rytForH iMavrLnisont tB n gPi oRnD4vdOraeulTergAsn- LCt iPs7k re–o PtFerrioonpm De rPetgeierpsat di–de iSrcsN D–IP eTgEhrRaesd S eaurnrsdp t roi sCinhge mical s and Conditions (https://onlinelibrary.w 1.2.4 Milestone 4: PROTACs on the Rise – Small-Molecule Degraders Achieve iley.com in vivo PoC 8 /term 111...222...567 MMMPriiiolllteeeesssitttnooo nnnLeeee v567e::: lSHBst euiycmko13niandng t AIhtfe tt eoPr rt Ahotelel Ma–s oaTnmP!D eM –ion Il neCcdluiunlcaiicrna Ggl TlPurreioasxl ism 1i01ty1 to Modulate s-and-conditions) on W 1.2.7.1 Itrsa TnPscDr iJputsiot nthael MBeogdiinfinciantgio?n B ifu1n5ctional Modulators of Post- iley Online L 21. 3 C R Ceeolfnleucrlleaunrsc iPeorsni n acn1ip9dl eOsu otflo Toakrg e1te7d Protein Degradation 25 ibrary for rules of use; O A 2222....1121.. 12 LU TJ BLoayyabãrsssoigooiq cessDu tooPiiemmatrdimin naeP-aslcPr nTiorptatoil2ernet6gieosnea o atsDifnon eTdmgga Derra goS2dery7iatssit ntiHeogmen Sl l fue(rUrbossmPcthSr amt)h teiees2 d Ct6oy ttohseo Pl arontde athsoem Neu acnledu s 29 articles are governed by the applicable C reative C om m ons L icense D ow nloaded from vi C22o..22n..t11en .1ts TRaerggueltaitnogr yto T tahreg ePtr Roteecarsuoitmmee nt2 929 https://onlinelibrary.w 2222....2223... 112.. 23 TTE Taaanrrrggggaeeegtttiei Enndggn D gtthoaeg geLe rPyamsrdooeatsnteoitoam bsnoye fm srt hoeme 3 U3 M3b2eiqmubitriannaeti-oEnn cMloascehdi nOerrgya ne3l1les and iley.com/doi/ by ibrahim 2.3.1 Dtheeg Eraxdtraaticoenll ufrloamr S tphaec eP las3m4a Membrane (PM) and the Extracellular ragab - C Space 35 ochrane G 2.3.1.1 Internalization at the PM and Endosomal Sorting 35 erm 2.3.1.2 Ubiquitination at the PM 37 any , W 2.3.2 Degradation from the Endoplasmic Reticulum (ER) 39 iley O 2.3.2.1 ER-Associated Protein Degradation (ERAD) – Proteoasomal Degradation nline L 222 ...334.. 23. 2 DfE C RrReooefnmg eLrcra yletudshnodaecsti eiEonosmgR n R ef5-reA0o3m9mssa ortkchisea tGe5do0 lDgie gr4a7dation (ERLAD) 46 ibrary on [22/12/2022]. See the T erm 33333.... 1112 .. 12 UEDR IG Snu3aeebtfb vnriaUqseoeebtuldrlroi aiuaqMtpltciu em.nC ti Ii tRoooeCirnnnneoic sct dL, re iKeupg6 ai6ata3tts3nmsh oedeefs r Tn iEanat3s era gMnLFeediotgre lrDadeiss ceeP uga rMrlnoaodterne cVM iRhninaae Dccncehoeinsiggnzmnroeai satdDi naao’Atdnnni do gRn iPeo6 gll5aeu6tlllf3aaotrimons fo6r5 Drug s and Conditions (https://onlinelibrary.w 3.2.1 Regulating E3 Ligases Activity 66 iley.com 3.3 RING E3 Ligases 67 /term 3333....3343.. .123 SID HnueEsbfiCiggnTrhio ttEuiso 3pinn sU taobn 6iRdq8 IuDNiitGsincso LRvieegrgayus elast6 i7o7n3 and Function 72 s-and-conditions) on W 3.4.1 Definition and Discovery 73 iley O 3.4.2 Subgroups 73 nline L 3333....4444....3444 ..12 SRIInnterttgueruarcmmltautoorilleoee nacc unulldaa7 rrM5 IIenncttheerraaanccittsiimoonn ss 747775 ibrary for rules of use; O A 333333......444455.... .45551. .. 312 ISPGI RnmtoIrrsNsoumitwg-Gctuhttr–unhtaIsrin B eStisyn Rialg at–nnotRdi7 aHo I9lMniNenacGegltc MFh(Rua7oBn9ndiRcisft)mii coa nt8si58o 5n7s 9 78 articles are governed by the applicable C reative C om m ons L icense D ow nloaded from 33..56. 2 I Cnosnigchlutss iionnto a Tndh eIinr sRigehgtusl aintitoon D arnudg FDuenvcetlioopnm e8n5t 86 Contents vii https://onlinelibrary.w References 87 iley.com 4 ATe Srntraurcyt uCoraml palnedx BFioorpmhaytsiiocna l P1e0rs7pective of Degrader Activity Through /doi/ by ibrahim 4.1 M Inotrrgoadnu cSt. iGonad d 1a0n7d Marine C. Aublette ragab - C 4.1.1 Mechanism of Degraders Through Ternary Complexes 108 ochrane G 4.1.2 Ternary Complex Behavior 108 erm 4.1.2.1 Binding Pose 108 any , W 4.1.2.2 Affinity and Cooperativity 108 iley O 4.1.2.3 Stoichiometry 110 nline L 444444......111111......223233. ....65412 FOPRBStlliebraeosusxspietcdihibrtecvyuiinlistrincyitacyyg ls B a1ni111o1d110l1 o10Q1guy an1ti1f2ying Ternary Complex Behavior 111 ibrary on [22/12/2022]. See the T erm 4444444.......2222222 ......111122. .. .1231 XPPPAMMRRR-soorsOOOalleeeyTTTscc sAAACuumCCCrllaayes-srrsnI - tRRnGGta deeolll uccuufSrr ecetSuurse-tuii IdrRttncuii nnTedtcuceggutrrur cvOuenreosieatdt nh-roi Gny TefH greuCT riEiCepondr3pmeaen rerdLaepyl ir–blD gyeCLlao exioCss nnSemio dgst(mrp anCuul pReoc1 lxPtfBe2u rxPS3NroetRe)trsse Ou icnT1t1 A1u2(11Vr9C34eH sD Le)g1 r2a81d1e4rs 127 s and Conditions (https://onlinelibrary.w 4.2.2.2 Molecular Glues Recruiting Other E3 Ligases 136 iley.com 4.3 Future Perspective on the Importance of Ternary Complexes in PROTAC /term 44 ..33..12 TE RDeaeirscfncehora e(vrTnyeec rCyren soa amnrdyp1 4lCDe3xoeemvse pl–ol epIsxm )S eteone tiIn tsg 1 OB3we9lnie vi1n4g2? 139 s-and-conditions) on W iley O 5 Computational Modeling of PROTAC Ternary Complexes and Linker nline L 5.1 DSJ Ienvestessrneiog dAJn. u. CMchti1ielol5nen1 ra , nGdr1i 5gJo1ohrini VK. aArnadnriicaonlaosv, Victoria Mischley, Khadija A. Wharton, ibrary for rules of use; O A 55555 .....23456 P C P EP L RRRRomeoofmOOOeekrTTTrpiegnAAAunigntCCCca gie stnTD s iMoe teorn1sen 1ait6tghah6l4 nre9Moy daF oCsnud odfteoum lOrri npeCpl gtoei xomm1ef6 ipsPz8 uaRtt1Oaiot5Tin3oA nCa1 lTl6ye2 rDneasriyg nCionmg panledx eOs pti1m56izing articles are governed by the applicable Creative C om m ons L icense D ow nloaded from viii C6o ntents Manodl eDceuslaigrn G lu1e7 D7egraders: From Serendipity to Hunting https://onlinelibrary.w 666...122 .1 NL I “nMuatitrsouo lNrdeaicuelu ctColtai-oorBm naG rplruoa1ued7”no7 ,dC Ason nac 1De7po9mt os1t7e9gui and Cristina Mayor-Ruiz iley.com/doi/ by ibrahim 66..22..11..21 MMoolleeccuullaarr GGlluuee sD e1g7ra9ders 182 ragab - C 6.2.2 Synthetic Compounds 182 ochrane G 6.2.2.1 Molecular Glues 182 erm 6.2.2.2 Molecular Glue Degraders 183 any , W 6.3 Synthetic Molecular Glue Degraders: Serendipitous iley O 6666....3334... 321 BHMMAD SyCciioonsgcLllchtoeeoh6m ccS veuuDehtmllireaaacigoprr eMr dseGGa a odClltuuleio1eoeer8mcns uDD4: plIeealnegg1rdmrr 8Gaau4eddcluneetierrtoass nD rHHi eotiiygfjj aa rPaccodkk1le8iiynnr6msgg: eCCIrnRRizteLLan44titCDoiRConBAn NFa 1(l15 I 8(MA8irDysl )S: uBlrfoonada mTaidrgees)t: nline Library on [22/12/2022]. See the T erm 6666....4444....1234 CPSβDAD-tryseerCoscvgusaalercpiytalnteeosdu n”cpKert imerin vsM- G1 eeMn9o uD21loties9ildc se2ecucdou1la v8lDrae8 rerG yvGl euollufeo epIDK mDeZgeeFrnga1rtda Modefre osHrl see cl1uio81lsa98 r8( IGKlZuFe 2D) eMgroaldeceursl avri aG “luUep s and Conditions (https://onlinelibrary.w 6.4.5 Discovery of VHL-Binding Molecular Glue Degraders 193 iley.com 6.5 Conclusions and Outlook 193 /term 7 T Rinae rNfgeeeruetenrodcde Pesr goet1ne9ien5r aDtievger aDdisaetiaosne sa s a2 0T5herapeutic Strategy s-and-conditions) on W Fleur M. Ferguson iley O 7.1 Introduction 205 nline L 7777....2222 ...111 ..12 HMTAaleipusthef oraol2-dbS0eyi6dfnu Punrccoltetioeininn asl 2T0a28r0g6eted Protein Degraders 206 ibrary for rules of use; O A 77777 .....22234... 123. 3 TKm M C RDoieHonfnPleatec-trsc4l eeuu3nssl 2 ciaa0oern29ns Gd 1 0lHu22eD11s21A C2s1 1210 articles are governed by the applicable C reative C om m ons L icense D ow nloaded from 8 IXniasiogyhut sZ haanndg Future Perspectives of Covalent Protein Degraders 2C1o5ntents ix https://onlinelibrary.w 888...122 .1 H I PPnrratoorlttooeePdiinnRu scOD tTieo2gAn1rCa 7d 2er12s51 t7hat Covalently Interact with the Substrate iley.com/doi/ by ibrahim 88..22..23 MKREATAS PG21 2aCnd B2T2K0 218 ragab - C 8.2.4 EGFR, ERK1/2, and ERRα 221 ochrane G 8.2.5 Monofunctional Protein Degraders 223 erm 8.3 Protein Degraders that Covalently Interact with E3 Ubiquitin any , W Ligases 224 iley O 8.3.1 RNF4 224 nline L 888888......333333......234567 SDDRKFPENECCSMAAAFB1P1FF21B1 114 61 2 22222722226237591 ibrary on [22/12/2022]. See the T erm 889 .. 45 TE OD RMxeeeuectfgtaeehlrnrnonaesoddon kitalncoo toegi gAosf i t nefLhfs eee 2fvc o32Dte7r 3reP a6Cgrgooriatnvedagial neCt niLootevn vPa eTrleoolsnto etl ikCn2it h4D –5eem mgriRsatdNreyAr f ToDarir sTgcaeortvgineergtye a ds P 2ar3no3 tAelitne rnative s and Conditions (https://onlinelibrary.w Andrei Ursu, Barbara Herdy and Hendrik Osadnik iley.com 9.1 Introduction 245 /term 9999....2333 ..12 AT L Spihbfleeeic rrCairnapygnce lutSe Sth iopcafl p SiEcetirusna ktgthae Iergmy iCeopset ailtclco’ stm sC T RthrhaNaennA Tsgcsre ra iPnp2rsto4octr7meipient o Lme2v4ee 8ls2 T4h9rough Splicing s-and-conditions) on W Regulation 251 iley O 9.3.2.1 Activating a Weak Splice Site in SMN2 to Increase Protein nline L 99..33..22..23 mPMOrlRooigddNouuAnlcau tDticionleneggo r ttaih2dde5ae 2tsMi o(KSnSN oOKfs H2) ITsT2o5 fbo3yr mIn Bdualcainncge A wbietrhr aSnptl iScpe lSicwinitgc hinin Hg D 252 ibrary for rules of use; O A 999999......343343. ....32213... 145 TP CINSnmaRyucrtOcaogollerTpelrt-AaleiManrcCs gtoRm- lSMGNeapclAtelouiidc cblDi eiRaan-eltMNg ecA daATeSy drD Qiwigaeugi2tgteea5rhdral5 is datN y NaM utCMicooolnlDenea tcoirrunf oD l Slat ehpMrc le“aie cGCyci nhlyougtafoe nCF”pi aUlstacmhGstaoms tR r D 3e2peB25ge157ra 7a(tS dEFex3sp BRa1nB)sM io32n95s 4 225535 articles are governed by the applicable C reative C om m ons L icense D ow nloaded from x C99o..44n..t12en. 1ts RHNarAn eBsisnindgin Ign Ptrroonteicin Pso Rlye(cAru) iAt cthtiev amtiRonN wA iDthe AgrSaOdast io2n5 M8 achinery 259 https://onlinelibrary.w 9999....4444....2333. ..112 RRSSmMNNaAAOl- lLIP-nM-RMteOoerlTdefecAirauCetlene-dMc E eUen (dphRiraaNentgAecudeil) maD –teei omngnrtia coodrffoa mmtRioNiicRnAr -oo1,R f2s Ni4LR IAiNNn AP2I8nr,o Afalcna eamdsns Admin SRagOtB o FrG2yOa6 Xp2m1 er2s5 9260 iley.com/doi/ by ibrahim 9.4.3.3 RDIisBeOasTeAsC -M26e3diated Degradation of Pre-miR-21 via Targeted Recruitment ragab - C of RNase L 263 ochrane G 9.5 Conclusions 265 erm References 266 any , W iley O 1111100000.... 1233 .1 TPBG I P EnhRreemtooyeOrteroo egFTrndigeuAndui t nMC cuDgtr . iVe e2BoHga 7nuorre3ra fits adeHlte2arieomt7otib3noeisnrf ou Bbn2eicf7ytuio5nonncdtai loC Mnaanolc dCeaorl mitip2eo7s 3ufonrd Ps:r oPtReOinT ADCesg raandda tion 275 nline Library on [22/12/2022]. See the T erm 11111110000000.......8915674 0 D M T H D H PaReeieorgggOtgdherreTuraajtoaAlddeacbaadCtkitti f-iiinAunIoognncnng escP Aooptthyiffiuo rlo ERaetnsotdxpNaipt ohlTAr hnCaoea crcogyehmy2ll2nla 88upot12ilolo2aou7nrgn 7 Pidersso2 8tBe1e2iny7os7 nd2 P7r9otein Degradation 281 s and Conditions (https://onlinelibrary.w 10.11 Potential Applications of Heterobifunctional Compounds to Modulate iley.com PTMS 283 /term 1101. 12 D R Ceeofsnetcrrleuuncstciieoosnn s w a2in8tdh3 Oa uPtulropooks e:2 T8a3rgeted Protein Degradation in Drug s-and-conditions) on W Discovery 289 iley O Paola Martinelli, Christiane Kofink, Georg Boeck, Harald Weinstabl and nline L 111111...111 ..12 M PTSeaRalrOnegcfeTrtteiAivdnCe gK sI o Pnienrhgo iDltbeirituniogsn Dt hoiasf tcI oDsovoefo rNrymo: Wts R hey2s?p9 o2n2d8 9to Inhibition 289 ibrary for rules of use; O A 1111111111111111........44443112 ... .. 11134 .. 12 S MTA TIP Rnearhorocorcyuaerllklletoen ileScadnidsnuusog ieogllpmeaf fiodiDr tniAn odGDM uaPpelums opPuAlrtlKyeiaeind ctn DDaCeiaoclstiehoynsi gocg a Bronosla3le fv ed0 fceEon3ea3rrfgrue0f sePeds1:s ceR D Mt oOosef of fT PilCAne2RcaiC9Otut3iasolT lanyArt, 2C iGAc9s l4dA uveca2 tDni9vt6eiatggyre asd,2 ea9rns3 d C30h1allenges 300 articles are governed by the applicable Creative C om m ons L icense D ow nloaded from 1111..44..12. 3 PBRCOL6T ADCegs rtahdaetr A BrIe- 3a8ls0o2 Mo3l0e3cular Glues: NX-2127 and KT-413 30C4ontents xi https://onlinelibrary.w 11111111....4444....3334 .. 12 RSTTcoaarr tGegioeelnnut-iaeBnl oa gDsr- eBiNsdaco soDtev idteso crD yoGi vsoleucfr oeMyv f:e ooDrrlye eT:cg aCurralDgaderKe tGre1sd2l uo PIfenr SoDh3tiee7bgi inMrtoa Drudsete aDrgnsre atg dβr3a-a0Ctdi5aoetn Ce nyic3nl0i n7 3K0 6305 iley.com/doi/ by ibrahim 1 1.5 T Raerfgereetendc ePsr ot3e0in8 Degradation: Here to Stay 307 ragab - C ochrane G 12 Taming the Beast: How to Optimize DMPK–PD Properties of Oral erm Degraders 313 any , W Caroline Rynn, Arthur Van De Vyver, Antje Walz, Carina Cantrill and iley O Matthias Wittwer nline L 111111222222......111111 .....12345 PTSPPPoehlhraarlyyusmnssmbsiieccpialaoooi btccPryhhitrl eoieetrmmtys3e i1iincc8aa33 Bll11 iaP57nnrdodip nAegrD tiMe3s1E 8 P3r1o4perties of Degraders 314 ibrary on [22/12/2022]. See the T erm 111111222222......211122.... .16782 PDCOS DPihKlrermeauag/alruPrg rmaA–lDaadDnba teCiccsrrooeuoosn rl:gn op P sIgt3iKniid31oct/2e9neaPr3rl aD aPtc i3rctoo2ihnoc0ansel sslDes enusgr3 ioe1nsf9g Da Dnedrgu rtaghd eDe Rrissoc aloenv odefr P yMK ao/nPddDe Dl iAnevgspe alenocpdtsm en32t 3 324 s and Conditions (https://onlinelibrary.w 12.2.3 Translational PK/PD and Human Dose Prediction for Targeted Protein iley.com Degraders 330 /term 1 123. 3 P G RReafOpesTr eAanCnc®de PFs ruott3ue3ri1en PDeergspraedcteirvse:s B ri3d3g0ing the Divide from Chemical Biology s-and-conditions) on W Tools to Clinical Candidates 337 iley O Erika M.V. Araujo and Keith R. Hornberger nline L 11113333....1234 I P Pinnhh tvyarisortimrdcouoa AcccthoDieokMmnin Eiect a3Aicl3 ssP7s raoy3ps4 e1rt3i4es2 339 ibrary for rules of use; O A 11113333....5678 I R P T C Cnohelodixfanneeirccixrmcloe uanlalosc c3iCgeoo6ysand1 s yen3 3S3a45t5m76u5dicise s 343249 articles are governed by the applicable Creative C om m ons L icense
The list of books you might like
