limiting789se.com

Introduction!
Theoceansoftheworldcoverroughly71%oftheplanetwithamediandepthof>3000mandameandepthof3800m.
Ofthisenormousex-panse,lessthan5%ofthedeepseahasbeenex-ploredinanywayandlessthan0.
01%ofthedeepseafloorhasbeensampledindetail[1].
Whatisalsoofsignificanceisthatofthe36animalphylaidentifiedtaxonomically,34arefoundinthema-rineenvironment[2]and,ofthese,approximatelyhalfareonlyfoundinmarineenvironments.
Oftheremainder,approximatehalfarebothmarineandterrestrial(thoughpredominatelymarine)andonlyone,thephylumOnychophora(thevel-vetworms),isexclusivelyterrestrial.
Althoughorganismshadbeenrecoveredfromrel-ativelyshallowdepthsinthe1800sandhadbeenseenformanycenturiesoncoralreefsandbeaches,notuntiltheChallengerexpeditioninthe1872–1876timeframe,andthentheGalatheaexpeditionin1950–1952whereliveanimalsfromthePhilippinesTrenchat10190m[3]werere-covered,wasitrealizedthatwiththepossibleex-ceptionoftheanoxiczonesintheBlackSea,livinganimalscouldbefoundatalldepths.
Thereasonforusing"possible"asamodifierinthesentenceaboveisthattheformaniferantubewormsfoundat"blacksmokers"areinanoxicenvironmentsandutilizemicrobesofthesulfurcycletosurviveandgrow.
Whofirstdecidedtoinvestigatethemarineenvi-ronmentasasourceofmedicamentsisunknown,butbothJapaneseandChineseherbalscontainedvariousmixturesthatwereusedaspartoftradi-tionalmedicine,andcertainlythetoxicpropertiesofmarine-derivedproductswerewellknowncenturiesago,withperhapsthebestknownex-amplebeingthepufferfish(Fugu)inJapanesecui-sine(thoughseethecommentsontetrodotoxinlaterinthisreview).
Fromahistoricalperspective,"TyrianPurple",adyestufffromaMediterraneanmolluskusedinRomantimes,actuallyhassignif-icantactivityinsomecancersandwasusedasapartoftraditionalChinesemedicine(TCM)forthetreatmentofleukemia.
Itisonlyrecentlythatitwasrealizedthattheactivechemicalcom-pounds(marinesourcedandplantsourced,re-spectively)wereofthesamebasicchemicalclassandmaywellbeofmicrobialorigininbothcases.
Thisarticlewilldealwiththepotentialofthema-rine(aquatic)environmentanditsorganisms,asleadstoagentsthathavebeenapprovedforuseagainstdiseasesofman(andinonecase,foruseinagriculture),bytherelevantagenciesofgov-ernmentsworldwide.
Thesewillbedrugs,notfoodsupplementsorfunctionalfoods,etc.
Wewilldiscussthosethatareapproved,areinclinicaltri-als,andshowwherethemoleculescamefrom,di-rectly,modifiedbysynthesis,oreventotalsynthe-sisbasedonamarine-sourcedcompound.
Inonecase,acompoundthathadbeeninclinicaltrialsAbstract!
Thepotentialofthemarineenvironmenttopro-ducecandidatecompounds(structures)asleadsto,orevendirectdrugsfrom,hasbeenactivelydiscussedforthelast50orsoyears.
Overthistimeframe,severalcompoundshaveledtodrugs,usuallyintheareaofcancer(duetofundingsour-ces).
Thisreviewisdesignedtoshowwheretherehavebeensuccesses,butalsotoshowthatinanumberofdiseaseareas,therearestructuresoriginallyisolatedfrommarineinvertebratesandfree-livingmicrobesthathavepotential,butwillneedtobe"adopted"bypharmaceuticalhousesinordertomaximizetheirpotential.
DrugsandDrugCandidatesfromMarineSources:AnAssessmentoftheCurrent"StateofPlay"AuthorsDavidJ.
Newman,GordonM.
CraggAffiliationNIHSpecialVolunteers,NaturalProductsBranch,NationalCancerInstitute,Frederick,MD,USAKeywordsl"marinesourceddrugsl"clinicaltrialsl"cancerl"HIVreceivedAugust20,2015revisedNov.
30,2015acceptedJanuary5,2016BibliographyDOIhttp://dx.
doi.
org/10.
1055/s-0042-101353PublishedonlineFebruaray18,2016PlantaMed2016;82:775–789GeorgThiemeVerlagKGStuttgart·NewYork·ISSN00320943CorrespondenceDr.
DavidJ.
Newman664CrestwoodRoadWayne,PA19087USAPhone:+16109719784Fax:+16109712526djnewman664@verizon.
net775NewmanDJandCraggGM.
DrugsandDrug…PlantaMed2016;82:775–789ReviewsThisdocumentwasdownloadedforpersonaluseonly.
Unauthorizeddistributionisstrictlyprohibited.
asanantitumoragenthasnowgainedanew"leaseonlife"asapo-tentialtreatmentforotherunrelateddiseases.
Whatwill,however,becomeobviousasthestoriesunfoldisthattheoriginalorganismfromwhichthecompoundwasisolated(usuallyamarineinvertebrate)mayormaynotbetheactualpro-ducerofthemetabolite(s)ofinterest.
Wherethetrueproducerisknown,itwillbeidentified,butinasignificantnumberofcases,theevidenceisstillcircumstantial,thoughinothercases,theor-ganismisdirectlyidentifiable.
TheEarlyRecord!
ThoughfoundinbothmarineandaquaticenvironmentsrangingfromtheSeaofJapantoLakeVictoriainCentralAfrica,onecanarguethatoneofthefirstgenerallyused"marine"invertebrate-sourcedsecondarymetaboliteswasthetoxinknownasnereis-toxin(l"Fig.
1)fromtheflatwormLumbrinerisbrevicirra(alsonamedLumbriconerisheteropoda).
Thiswormhadprobablybeenusedforcenturiesbyfishermentostunfishwithinthelake,thuspermittingthemtoharvesttheircatchesrathereasily.
Itmightalmostbecalleda"chemicalequivalent"ofthedynamitefishingsystemusedbyfishermenincountriessuchasthePhilippinesandotherareasofSEAsia.
Inaddition,Japanesefishermenhadknownforyearsthattheflatwormhadanti-insecticidalproper-ties,asitkilledcarnivorousinsectswhentheylandedonit.
In1934,Nittaisolatedtheactiveprincipleintheflatworm,withastructurebeingproposedbyOkaichiandHashimotoin1962andconfirmedbytotalsynthesisasreportedbyHagiwaraetal.
in1965[4].
Thiscompoundwasshowntobeanacetylcholinean-tagonistandoverthenextfewyears,insecticidesweredevelopedfromthebasestructure,withacloseanalogue,Padan(l"Fig.
1),beingmarketedbyTakedain1967.
Therehadbeensporadicreportsfromatleasttwomillenniaagoofpharmacologicallyactiveagentsbeingisolatedandidentifiedfrommarineorganisms;but,itwasnotuntilthemiddleofthe20thCenturythatanyformofsystematicinvestigationoccurred.
Thus,intheearly1960stoearly1970s,academicgroupsintheUSA,andpharmaceuticalcompany-linkedorganizationssuchastheRocheInstituteforMarinePharmacologyinAustralia,re-portedtheirfindingsinavarietyofformats.
Thebestsourceforinformationontheseandearlierstudiesisprobablythe1976re-viewbyRuggieri,whichshouldbeconsultedbyinterestedread-ers[5].
Arabinose-containingnucleosidesOnemayargue,andtheauthors(inanewsinterviewintheearly1990s)andanotherhavedoneso[6,7],thattheseminaldiscov-eries,andthustheimpetusfortheinvestigationofmarinebiodi-versityandthesubsequentvisionofmarine-deriveddrugsonthemarket,canbetracedtotheidentificationbyBergmannintheearly1950softhearabinose-containingbioactivenucleosidesspongothymidineandspongouridine(l"Fig.
1)fromtheCaribbe-anspongeTethyacrypta[8–10].
Thesediscoveriesoverthrewthethencurrentdogma;anucleosidehadtohaveeitherriboseorde-oxyriboseasthesugarmoietyinordertodemonstratebiologicalactivity.
Thus,cytosinearabinoside(Ara-C,cytarabine,l"Fig.
1),averywell-knownandprescribedantitumoragent,thoughnotorigi-nallyfoundinsuchamarineenvironmentas"Ara-C",cantraceitschemicallineagebacktothediscoveryofbioactivenucleo-sidesthatcontainedarabinoseratherthanriboseordeoxyribose.
Thoughwewerenotthefirsttorecognizetheimportanceofsuchsubstitutions,since,asmentionedearlier,Suckling,inareviewinajournalthatwasnotwellknown[6],reportedonthechemistryinvolvedinthesynthesesoftheseandothersucharabinose-linkednucleosideswithcommonoruncommonbases,wewereperhapsthefirsttoformallylinkthediscoveriesofthemarine-sourcednaturalarabinosesbytheBergmanngrouptothe"de-sign"ofthisagent.
So,Ara-Ccanbelegitimatelyconsideredtobeamarine-derivedagent,sincewithoutarabinoseinplaceofdeoxyriboseorribose,itwouldsimplyhavebeenanormalcom-ponentofnucleicacids.
Asofthe15thofAugust2015,thereare828trialslistedintheNIH(NationalInstitutesofHealth,Bethesda,Maryland,USA)clin-icaltrialsdatabase,with262ofthembeingopenstudiesthatarerecruitingandcoveringalargenumberofcancers,rangingfromPhaseIVdowntoPhaseI.
InthecorrespondingEuropeandata-base,127clinicaltrialscoveringthesamephases,butwithsomeoverlap,arelisted,andintheWorldHealthOrganizationdata-base,justlookingatAustralasia,thereare17opentrialsnotdu-plicatedintheothertwodatabases.
Aswithotherwell-knownapproveddrugs,cytarabineisstillinuse,morethan40yearsafteritsinitialapproval,withaninterestingrecentpaperquestioningtheuseofhigh-dosecytarabinetherapyduringremissioninadultswithacutemyeloidleukemia[11].
Othercloselyrelatedcompoundssuchasadeninearabinoside(Ara-A;l"Fig.
1),anantiviralcompoundsynthesizedandcom-mercializedbyBurroughsWellcome(nowGlaxoSmithKline),werebaseduponthearabinosesubstitution,butincontrasttoAra-C,thiscompoundwaslaterfoundintheMediterraneangor-gonianEunicellacavolini[12],andthuscouldbeconsideredanaturalproduct,eventhoughitwassynthesizeddenovobeforeitsdiscoveryinthegorgonian.
Similarreasoningrelatedtoun-usualsugarsandbioactivityledtoinvestigationsonthemini-mumsizeofsugarringsandtheeffectofothersubstitutionsonthesugarring(s);thusazidothymidine(AZT;l"Fig.
1)andevenacyclovir(l"Fig.
1)canbetracedbacktothisinitialdiscovery.
Veryrecently,agroupofinvestigatorsattheScrippsInstitutionofOceanographyreportedthatastrainoftheGram-negativebacte-Fig.
1Earlyagentsfrommarinesourcesandtheirsubsequentderivatives.
776NewmanDJandCraggGM.
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Unauthorizeddistributionisstrictlyprohibited.
rium,Vibrioharveyi,whichwasisolatedfromthespongeTectite-thyacrypta(thecurrentnameforthespongethatBergmannusedinthe1950s),producedspongosineandspongothymidine(l"Fig.
1)amongstothernucleosidesonfermentation[13].
Whetherthemicrobeistheonlyproducerhasnotbeenconclu-sivelyproven,theremaybeinterplaybetweenthemicrobeandthespongehost,butitisextremelysuggestiveasotherrelatedmaterialswereobtainedfromotherstrainsofthemicrobe,andaputativespgbiosyntheticclusterwasidentifiedinthemicrobesDNA.
History!
Bythemiddle1960s,theterrestrial"plantworld"hadbeenrea-sonablywellexploredfornovelanticancerdrugcandidatesandreportedonbyanumberofgroups,withagentssuchastheVincaalkaloidsfirstbeingreportedaspotentialantitumoragentsinthelate1950s.
Similarly,theterrestrialmicrobialworldhadbeenex-ploredinasomewhatsystematicfashion,fromroughlythelate1940s,withsuccessinbothantibioticandantitumorareas.
Anumberofagentsfrommicrobialsources,orsuccessorsutilizingtheirpharmacophores,whicharestillincurrentclinicaluse,werefirstidentifiedinthelate1950stoearly1960s,mainlyinconcertwithindustry.
Goodexamplesbeingtheanthracyclinesincancer,penicillins,andcephalosporinsandtheirthousandsof"chemicaloffspring",allwithabeta-lactamringasantimicro-bials,ortheantimicrobialcarbohydrate-basedaminoglycosides,someofwhichhavegaineda"newleaseonlife"asmolecularbi-ologytoolsratherthanantibiotics.
Althoughtherehadbeenanumberofreportsofbiologicallyac-tiveagentsfrommarine(andfreshwater)environments(cfdis-cussiononarabinosidesabove),predominatelybyacademicre-searcherswhoreceivedfundingfromeithertheNationalInsti-tutesofHealth(NIH)componentinstitutesortheNationalSci-enceFoundation(NSF)forbasicresearch,nosystematicexplora-tionshadbeenperformedofmarineenvironmentsassourcesofstructuralordirectleadstomedicaments.
Startingintheearly1960s,theNationalCancerInstitute(NCI),thelargestinstitutewithintheUSgovernmentsNIH,expandeditshorizonsbeyondthetestingofsyntheticcompoundsasexper-imentalantitumoragentsandbeganlarge-scalestudiesofnatu-ralproducts.
Plantmaterialswerecollectedandrecollectedwhenrequired(andiffeasible)inconjunctionwiththeUnitedStatesDepartmentofAgriculture(USDA).
Microbialproductswereusu-allyprovidedbypharmaceuticalcompaniesandsmallnumbersofmarineinvertebrateswerealsoobtainedbypurchasefromcommercialcollectors.
Thesematerialswerethenextractedbypredominatelyacademicgroups,theextractstestedinitiallyinwholeanimalmodels(mouseandrattumors)andlaterinfast-growingmouseleuke-miacelllines(P388andL1210)bycontractorlaboratoriestotheUSgovernment,with"activematerials"thenbeingisolatedandidentifiedbytheacademiccollaborators.
Atthesametime,aca-demicinvestigators,includingthosewhowerealsoactingasNCIcollaborators/contractors,werealsoexpandingtheirinvestiga-tor-initiatedgrantapplications(knownasR01grants)towardsthemarineenvironment,withtheaimofcollectingandutilizingmarineinvertebratesassourcesofdrugleads(marinebiodiscov-ery).
ApprovedMarine-DerivedAntitumorAgentsand(Chemically)RelatedCompounds!
Asimpliedbythetitleofthissection,iftherearerelatedcom-poundsthatenteredclinicaltrialstheywillbediscussedaftertheapprovedagentwithnotesastotheircurrentstatus.
Exam-plesasdiscussedbelowincludetheMAb-linkedagentsinvolvingdolastatinderivativesandmoleculesrelatedtoET743.
Dolastatin-derivedapprovedagent(Adcetris)andrelatedantibody-drugconjugatesOneofthetwoantitumorcompoundsthatcamefromwhatmightbeconsideredtheearliestsystematicinvestigationsofthemarineenvironmentforsuchagents,asdistinctfromfindingac-tivitiesforisolatedcompounds,wasdolastatin10(l"Fig.
2),oneofaseriesoflinearandcyclicpeptidesisolatedfromtheherbivo-rousseahareDolabellaauricularia.
Theextensiveisolation/syn-thesisprogramsandthenclinicaltrialsinmanoverthenext20plusyearshavebeengivenindetailbytwooftheearlycoinvesti-gatorsandshouldbeconsultedfordetailsifdesired[14,15].
Sub-sequently,thedolastatinswereshowntobeproducednotbytheanimalbutbyacyanobacteriumofthegenusSymploca[16],thoughveryrecentlythisorganismwasrenamedintothenewgenusCaldoraandspeciespenicillata[17].
Noneofthedolastatins,includingdolastatin10,progressedbe-yondPhaseIIclinicaltrialsastheisolatedcompound,whichwasinitiallysynthesizedduetotheverylowlevelsfoundintheani-mal.
Avarietyoflaterchemicalvariationsalsoenteredclinicaltri-als.
TheseincludedauristatinPE(trialsunderthenamesofsobli-dotin,TZT-1027,orYHI-201),cemadotin,andsynthadotin(alsoknownastasidotinorILX-651),butnoneproceededbeyondPhaseIorearlyIIlevels.
However,duetotheveryhighpotencyoftwovariationsonauri-statin,compoundslaterknownasmonomethylauristatinE[MMAEorvedotin(l"Fig.
2)]anditsphenylalaninevariant,mono-methylauristatinF[MMAF(l"Fig.
2)],SeattleGeneticswereabletolinkspecificmonoclonalantibodiestobothofthese"war-heads",leadingin2011totheapprovaloftheantibodydrugcon-jugate(ADC)Adcetris(l"Fig.
2).
Thevastamountofworkre-quired,firstinoptimizingvedotin-basedwarheadsandthende-velopingthelinkersthatcoupletheantibodytothecompounds,wasdescribedbyDoroninaetal.
in2006[18].
Someoftheseweredesignedtoreleasethewarhead(vedotin)bysimplehydrolysisofalinkerbond,whereasothersrequiretheenzymaticdigestionoftheantibody,releasingthewarheadplusappendages.
Adcetris,alsoknownas"cAC10-vcMMAE",consistsofahuman/mousemonoclonalantibodylinkedto8valine-citrulline-MMAEmoleculeswheretheMAbwasdirectedagainsttheCD30epitopeexpressedinleukemiccells.
TheagentwasapprovedbytheFDAin2011andsubsequentlyapprovalwasgivenintheEUlatein2012andlaunchedintheUKinearly2013,allforCD30positiveleukemias.
Fullexplanationsofthemethodologiesusedandtheutilityofthisagentagainstavarietyoflymphomaswerepub-lishedinthe2010–2013timeframeandshouldbeconsultedbytheinterestedreader[19–22].
Inlate2013,theauthorslistedtheextensivenumberofMMAEandMMAFantibodyconjugatesthatwereinclinicaltrials[23],andoncheckingtherecordsapproximately20monthslater,asexpected,"trialattrition"hasoccurred,withthenumbersnowreducedtosixMMAEMAbcompounds(fourinPhaseIIandtwoinPhaseI)withoneMMAFMAbinPhaseI.
Inlate2014,Smagloetal.
publishedanexcellentreviewonADCsdiscussingothersin777NewmanDJandCraggGM.
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additiontotheMMAE/Fseries,whichshouldbeconsultedforgeneralandspecificstudies[24].
Currently(August9th,2015),thefollowingagentsutilizingMMAE/Faswarheadsarestillin"activeandrecruiting"clinicaltrialsandtheirstatuswillbediscussedinbriefinthefollowingsection.
Thus,asmentionedabove,aconsiderablenumberofthemoleculeslistedintheearly2014MarineDrugsreview[23]arenotincludedastherearecurrentlynotrialsfallingunderthesecriterialistedinanyofthegovernmentaldatabases.
Sinceinthemajorityofcasesresultsarepublishedwellafterthetrial(s)havefinished,noupdate(s)is/arefeasibleatthisstageastowhycom-poundsweredroppedfromclinicaltrials.
Glembatumumabvedotin(PhaseII)Inthiscombination,MMAEislinkedtoafullyhumanmonoclonalantibodyCR011(ananti-CG56972)viathevaline-citrullinedi-peptidelinkerasinAdcetris.
Itwasinitiallytargetedagainstpa-tientswithunresectablemelanomasatstageIIIorIVwhohadfailedonecytotoxicchemotherapyregimen,andwasthenex-pandedtoincludemetastaticbreastcanceraswell.
Thecombina-tionhashadavarietyofnamesduringitsevolutionincludingCDX-011,CR-011,andCR011-vcMMAE,sosearchingfordatacanbeatriflechallenging.
Theinitialreportoftheuseofthiscombinationwasgivenbyin-vestigatorsfromCuraGenin2006[25],followedbyareportofxenograftactivityin2007fromthesamegroup[26].
Thepoten-tialofthemonoclonalstargetintriplenegativebreastcancerwasdescribedin2010byRoseetal.
[27],andthecorrespondingdetailsinmelanomaweredescribedin2012byagroupfromthePeoplesRepublicofChina[28].
Currently,threecompletedstud-iesatthePhaseI/IIlevelsarereportedintheNIHclinicaltrialsdatabasewitharecentdiscussiononthemanagementofmeta-staticbreastcancerwiththisagentbyVaklavasandForero[29].
Therearereportsofclinicalactivityinbreastcancerpatients[30,31],andareportofclinicalefficacyinadvancedmelanoma[32].
Thereissomedichotomyastotheclinicaltrialstatusofthiscompound,butusingtheclinicaltrialsdatabasefromtheNIHandtheCelldexwebsite(http://www.
celldex.
com/pipeline/pipeline-overview.
php),asofAugust11th2015,thecompoundislistedasbeingatPhaseIIwithanewindicationshowingre-currentorrefractoryosteosarcoma(NCT02487979).
Pinatuzumabvedotin;DCDT-2980S(PhaseII)ThisADCfromGenentechisahumanizedIgG1antibodydirectedagainsttheCD22epitopeexpressedinleukemias.
ThewarheadislinkedinasimilarmannertothatusedinAdcetris,andreleasesmonomethylauristatinEonproteasecleavage.
Amodifiedsafetyprotocolwasusedinthedevelopmentofthisagent,astheCD22epitopeisnotexpressedinrodents,sotrialsforsafetywereper-formedincynomolgusmonkeys,anddemonstratedadequatesafetyinprimatesplusefficacyinxenografts[33].
Currently,thereisonePhaseIItrialrecruitingintheNIHclinicaldatabase(NCT01691898)andoneduplicativerecordintheEUequivalent(www.
clinicaltrialsregister.
eu/ctr-search/searchquery;EudraCTnumber2011–004377–84).
Thistrialisinnon-Hodgkinslym-phoma,notsolidtumors.
Polatuzumabvedotin;DCDS-4501A(PhaseII)ThisisalsoaGenentech/Rocheproduct,andisanADCwithmono-methylauristatinElinkedtoananti-CD79bmonoclonal.
Itiscur-rentlyinthesamePhaseIItrialasDCDT-2980S(NCT01691898)asanalternativetreatmentagainstnon-Hodgkinslymphoma,andisalsoinanongoingPhaseIItrial(NCT02257567)againstvar-iouslymphomasinadoseescalationstudy.
Inaddition,thereisaPhaseItrialagainstB-cellnon-Hodgkinslymphoma(NCT01992653).
AswiththeRocheagentabove(EudraCTnumber2011–004377–84),noothertrialsarelistedintheEUdatabase.
Lifastuzumabvedotin;DNIB-0600AorRG-7599(PhaseII/I)ThisADCisahumanizedIgG1monoclonalantibodydirectedagainsttheNaPi2bepitopelinkedtovaline-citrulline-monome-thylauristatinE.
TherearethreeclinicaltrialsshownontheNIHsite.
NCT01995188isaPhaseItrialagainstovariancancer,NCT01363947isanotherPhaseItrialdirectedagainstnon-squa-mousnon-smallcelllungcancerandovariancancer,andthethird,NCT01991210,isaPhaseIItrialagainstovariancancer,ep-ithelial,tumors,peritonealneoplasms,andmalignantfallopiantubecancer.
Tworeportsinabstractformhavebeenpublishedtodate,onefromthe2013AmericanSocietyforClinicalOncol-ogy(ASCO)meeting[34],andonefromthe2014EuropeanSoci-etyforMedicalOncology(ESMO)meeting[35].
DSTP-3086S(RG-7450;thio-antiSTEAP1-MCvc-PAB-MMAE;PhaseI)ThisisaGenentech(Roche)ADCusinganantibodyagainstahumanizedanti-STEAP1IgG1antibody,whichwasmodifiedviadetermination/modificationofreactivethiolsaccordingtothepatentapplicationbyBhaktaandJunutula[36],andthencoupledtothestandardvaline-citrulline-linkedMMAE.
Theantibodyisdirectedagainstthesix-transmembraneepithelialantigenofprostate1,hencetheSTEAP1acronym,andwasinitiallyevaluatedasthebasicADCwiththevc-MMAEwithanunmodifiedMAbandthenthethio-modifiedantibody.
Thedecisionwasmadetoproceedwiththethio-modifiedversionfromthePKdetermi-nations[37,38].
Currently,thereisonePhaseIstudyrecruitingpatientswithmetastaticcastration-resistantprostatecancer(NCT01283373)withpreliminaryreportsshowingsomeclinicalresponsesgivenatthe2013and2014ASCOMeetings[39,40].
Fig.
2Dolastatin-derivedapprovedagent(Adcetris)andrelatedanti-body-drug.
(Colorfigureavailableonlineonly.
)778NewmanDJandCraggGM.
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HuMab-TF011-vcMMAE(HuMax-TFADC;TF-011-MMAE;PhaseI)TF-011-vcMMAEisanADCunderclinicaldevelopmentbyGen-mabandSeattleGeneticsforthetreatmentofsolidtumors.
Itiscomposedofahumantissuefactor(TF)specificantibody(TF-011),linkedtovaline-citrulline-MMAE.
ThisADCiscurrentlyinaPhaseIsafetystudyagainstovarian,cervical,endometrial,blad-der,prostate,esophageal,andnon-smallcelllungcancersundertrialnumberNCT02001623.
TheNIHwebsiteshowstrialsintheUSandtheEU(UKandDenmark,butthereisnocurrentrecordintheEudraCTdatabase).
GSK2857916(J6M0-mcMMAF;PhaseI)Currently,thisADCistheonlyMMAF-linkedcombinationinclin-icaltrials,andunliketheMMAE-basedADCs,thisADCusestheproteasestablemaleimidocaproyl(mc)linkertechnologyasde-scribedbyDoroninaetal.
in2006[18]ratherthanthemorecom-monproteasecleavablevaline-citrullineversion.
Asofthetimeofthiswriting,thisADCisinoneclinicaltrial(NCT02064387),anopen-label,doseescalationwithsitesintheUSA,Canada,andtheUK.
Thepatientsdesiredforthistrialwillhaveoneofthefollowing:relapsed/refractorymultiplemyelomaorotheradvancedhematologicmalignanciesthatexpressB-cellmaturationantigen(BCMA).
Thisantigenisamemberofthetu-mornecrosisfactorreceptorsuper-family(TNFRSF17),whichisknowntobeselectivelyinducedduringplasmacelldifferentia-tionandiseffectivelyabsentonnaiveandmemoryBcells.
ET743[EMEA-Approveddrug(Yondelis)]andRelatedCompoundsinClinicalTrials!
Thiscompoundcouldbeconsideredthe"posterchild"forma-rine-derivedantitumoragents.
Thereasonisthatcurrentlyitistheonlymoleculeinuseasanantitumoragent,identicaltoacompoundoriginallyisolatedfromEcteinascidiaturbinata.
Theevolutionofthisagentfromthediscovery,preclinical,andclini-caldevelopmentfollowedatortuouspath.
Itutilizedmaterialsfrommassivedirectcollectionsofthe"producing"tunicateintheCaribbeanandMediterraneanseas,in-seaandonlandaqua-culture,andfinally,semi-synthesisfromaprecursormolecule,cyanosafracinB,obtainedbyfermentationofamarine-derivedmicroorganism.
Theinitialreportsofbioactivityinthisorganismin1970werefirstreportedbySigeletal.
[41],whichwasthenfollowedbytheinitialidentificationofthe"ecteinascidinseries"byHoltinhisPhDthesisin1986[42].
FurtherworkbytheRinehartgroupattheUniversityofIllinois(UrbanaChampaign,Illinois,USA)andtheWrightgroupatHarborBranchOceanographicInstitution(FortPierce,Florida,USA)ledtothesimultaneouspublicationin1990ofthestructureofET743andassociatedmolecules[43,44].
ET743waslicensedtotheSpanishcompanyPharmaMarfollow-ingthedemiseoftheUSbiotechcompanySeaPharmin1988,andthesubsequentsemisyntheticworkonthiscompoundwaswelldescribedbytheinvestigatorsatPharmaMarin2009[45],andaspartofadiscussiononthedevelopmentofmarine-sourceddrugentitiesin2012[46].
Bothofthesereportsdemonstratedthepowerofsemi-synthesisandoptimizationofprocessestoob-tainactivedrugprinciples.
ThemoleculewasapprovedintheEuropeanUnion(EU)in2007fortreatmentofadvancedsofttissuesarcoma(STS).
Currently,itisapprovedinover70countriesasmonotherapyforSTSandinanumberofcountriesfortreatmentofrecurrentplatinum-sensi-tiveovariancancerwhencoupledtoliposomaldoxorubicin.
In2009,thecorrespondingUSFDAapplicationfortheSTStreat-mentwaswithdrawn.
However,inFebruary2015,itwasac-ceptedforpriorityreviewforSTSintheUSAfollowingsubmis-sionofaNewDrugApplication(NDA)inlateNovember2014.
Themechanismofaction(andtheremaywellbeothers)isre-latedtotheexcisionrepaircomplexasdescribedbySoaresetal.
in2007[47].
In2014,DIncalcietal.
publishedanexcellentshortreviewonthecurrentstateofknowledgeofthemechanism(s)ofaction,andtheystatedinthatreviewthat"trabectedinnotonlyinhibitsthegrowthofcancercellsbutalsoaffectsthetumourmi-croenvironment(TME)bylimitingthenumbersofmacrophagesandbyinhibitingtheproductionofmacrophageproductsthateventuallypromotetumourgrowth"[48].
Thecommonalitiesanddifferencesinthepharmacologicalre-sponseoftrabectedinanditscloserelatives,zalypsisandlurbi-nectedin(l"Fig.
3;videinfra),werediscussedin2013withre-specttotheirexperimentaleffectupontheFanconianemiapath-way.
Martinezetal.
[49]demonstratedthatthesethreerelatedagentsinhibitedtheFanconianemiapathwayinthecelllinestested,increasingtheirsensitivitytomitomycinC.
Thisisincon-trasttomitomycinCbyitself,whichinthesamecelllinesalwaysactivatedthatpathway.
Theauthorssuggestedthatasaresultofthesefindings,thesethreeagentsmightbeusefulclinicallyin"Fanconizing"cancercellsinordertogainsensitivityagainstoth-erantitumordrugs.
Thesameyear,Romanoetal.
[50,51]reportedthatininvitroandinvivomodels,norelationshipwasfoundbetweentheinvitrocytotoxicpotencyandinvivoantitumoractivityinsyngeneicmousemodels,suggestingthattheremightwellbeahostre-sponseinthesemodels.
Also,thepharmacokineticsdiffer,evenbetweenthequitesimilartrabectedinandlurbinectedininhu-mans,andasexpectedduetothedifferencesinstructure,Zalyp-sishasbeenshowntodifferinpharmacokineticsinhumans[52].
AsofAugust12th,2015,therewere20openstudiesfoundforET743intheNIHclinicaltrialsdatabase,fiveatPhaseIII,eightatPhaseII,oneatPhaseI,andsixthatwerenotgivenaPhasedesig-nation,withcancertypescoveringbreast,prostate,softtissuesarcoma,andosteosarcoma,plusgeneralcarcinomas.
SearchingthecorrespondingEUClinicalTrialsRegister(database),26trialswerelistedfrom2006to2015witheightbeingPhaseIItrialsnotfoundontheNIHsite.
Theselistingsdemonstratethatonceacompoundhasbeenapprovedfortreatmentofonetypeofcan-cer,itwillbeplacedinclinicaltrialsformanyothers,eitherindi-viduallyoraspartofanewdrugregimen.
AdiscussionoftheevidenceandprobabilitiesofET743anditscongenersbeingproducedbyasyetunculturedmicrobesassoci-atedwiththesourcetunicatewaspublishedbyGiddingsandNewmanin2013[53].
ThatthisisinfactthecasewasconfirmedbytheveryrecentpublicationbytheShermangroupattheUni-versityofMichiganidentifyingthemicrobegenetically[54].
Thisisthesecondpaperusingisolationandgeneticanalysisofanasyetunculturedmicrobetoprovethepresenceofthebiosyntheticcluster(s)ofthesecondarymetabolitesfoundinthemarinein-vertebrateinthemicrobe,withthefirstbeingtheseminalpaperbythePielgrouppublishedinNatureinearly2014[55].
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Lurbectedin(PM01183;PhasesI–III)ThiscompoundisanothervariationonthebasicstructureofthedimericisoquinolinealkaloidssuchasET743,butwithatetrahy-dro-β-carbolinemoietyinsteadofthetetrahydroisoquinolinepresentinringC,andlikeET743,itbindsintheDNAminorgroove[56].
ThecompoundhaddifferentpharmacokineticsinpatientstoET743andattenuatednuclearexcisionrepair(NER).
Italsohadsynergywithplatinum-basedagentsinvitro,whichsuggestedapotentialtreatmentregimen,asitalsodemonstratedactivityagainstplatinum-resistantcelllines[57].
AsofAugust12th,2015,thereare10openclinicaltrialsontheNIHsite,oneatPhaseIII,fouratPhaseII,andfiveatPhaseI,plusonePhaseII(inSpain)ontheEUsitethatisnotduplicatedontheNIHsite.
PM-10450(Zalypsis;PhaseII)Thiscompoundisyetanothervariationonthebasicstructureofthedimericisoquinolinealkaloids,andwasderivedfromthestructureofjorumycin,acompoundisolatedfromtheskinandmucinofthenudibranchJorunafunebris[58],andrenieramycinJ(l"Fig.
3)fromaspeciesofthemarinespongeNetropsiasp.
[59].
ZalypsiswassynthesizedbyworkersatPharmaMarusingtech-niquessimilartothosedescribedfortheET743synthesisfromsafracinB[60].
ThemolecularpharmacologyofthisagentwasdescribedbyLealetal.
in2009and,surprisingly,thoughithasacloseresemblancetoET743,itdoesnotactivatetheDNAdamagecheckpointresponse[61].
ThereisadichotomybetweenthePhamaMarwebsiteandtheEudraCT(EU)websiteastostatusofthecompound.
OnthePhar-maMarsite(www.
PharmaMar.
com;accessedAugust12th,2015),thiscompoundisnotlistedasbeinginanytrials.
However,ontheEUsite,thereisstillalistingunder2009–016054–40ofanon-goingPhaseIItrialinSpain.
Noopentrials,however,areshownontheNIHsite,soitisfeasiblethatthiscompoundisbeingdropped.
Eribulin,(Halaven;E-7389),ahalichondrinBderivativeThisagentisawhollysyntheticmoleculemodeledonalittleoverhalfofthestructureofthenaturallyoccurringantitubulincom-poundhalichondrinB(l"Fig.
4),specificallytheringplusasmall"carbontail".
Thismoleculecamefromatour-de-forcebaseduponthesyntheticmethodforhalichondrinBfirstreportedbyKishisgroupin1992[62].
Duringthissynthesisandtheinvesti-gationbyscientistsattheEisaiResearchInstitute(ERI)inWo-burn,Massachusettsofthesyntheticintermediates,KishiandERIscientistsrealizedthattheactivepartofthemoleculeresidedinthemacrolidering(approxMWof600)andnotinthe"tail"(theremaining400+oftheoverall1000+MW).
ChemistsattheERIworkingverycloselywiththeKishigroupsynthesizedover200moleculesand,inconjunctionwiththeDevelopmentalTher-apeuticsProgram(DTP)atNCI,theychosethemodifiedtrun-catedmacrocyclicketone(eribulin,E-7389;l"Fig.
4)asthecandi-datecompoundwhencomparedininvitroandinvivostudiestopurehalichondrinB(obtainedbyDTPinconjunctionwithNewZealandscientists).
Muchfullerdetailsofthesyntheticandbasebiologicalinformationwerepublishedbytheleadersofthesyn-theticstudiesin2005[63].
Thisreviewarticleshouldbereadbytheinterestedreaderforfullerdetailsoftheevolutionofthiscompoundthroughearly2005.
Eribulin,aswiththe"naturalproductparent",isatubulininter-activeagentwithverypotentactivityatthenanomolarlevelininvitrostudies.
In2005,Jordanetal.
[64]demonstratedthatsup-pressionofmicrotubulegrowthwastheprimaryantimitoticmechanismoferibulin,withdifferentialeffectsduetothecon-centrationwhenstudiedinMCF7cells.
Atlowconcentrations,eribulinpotentlyinhibitedmicrotubuledynamics,resultinginaprolongedarrestofmitosisandinducingapoptosis,whereasattenfoldtheIC50value(orhigherconcentrations),itinducedde-polymerization[64,65].
Laterworkdemonstratederibulinsin-teractionwithcentromeredynamics[66].
Fig.
3ET743andrelatedcompounds.
Fig.
4Eribulin(Halaven;E-7389)andmodifications,halichondrinB.
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ThattheactualinteractionoferibulinwithtubulinmaybeevenmorecomplexthanwasoriginallythoughtisshownbythedatareportedbyJordansgroupina2010paper[67].
Using3H-eribu-lin,theyfoundaveryhighaffinitysite(Kd400±200nM)on25%ofthetubulinmass(whichmightbetheαβIIItubulindimer),withastoichiometryof0.
26±0.
12molesoferibulinpertubulindimer.
Anotherhighaffinitysite(Kd3.
5±0.
6M;stoichiometryof14.
7±1.
3eribulin:tubulindimer)wasalsoidentifiedtogetherwithalowaffinitysite(Kd~46±28M;stoichiometryof1.
3±0.
4satu-rablesitespertubulindimer).
Thebindingisothermfromtheseresultsishighlycomplex,whichmightwellbeduetothecompetitionforeribulinbetweensolu-bletubulinandmicrotubules,thoughthereisphoto-andelec-tron-micrographicevidenceinthepaper,andinearlieronesfromthesamegroup,forbindingtotheplusendofmicrotubulesandpreferentiallytoβ-tubulin.
Asmentionedinthepaper[67],fur-therexperimentationwillberequiredtoexplainthesecomplexresults.
In2007,areviewbyWangetal.
[68]gaveextensivecoverageofthepatentroutestoeribulin,withsomeduplicationoftheworkpresentedinthe2005reviewbyYuetal.
[63].
Then,in2009,threepublicationsfromtheKishigroupdetailedimprovedmeth-odsforthesynthesisoferibulin.
Thoughthesepaperswerewrit-tenfromanacademicperspective,theyconsideredtherelativecostsofproduction[69–71].
Followingonthesyntheticstories,twoexcellentreviewswerewritteninearly2009bythePhillipsgroupattheUniversityofColorado,coveringthepublishedsyn-thesesbymanygroupsofhalichondrinB,norhalichondrinB,anderibulin[72,73].
Thesepaperswerethenfollowedbythreear-ticlesin2013thatcoveredtheprocesschemistryinvolvedinpro-ducingmultihundredgramquantitiesundercGMPconditions[74–76],andtheoverallstorybytheleaderoftheinitialchemicalsynthesis[77].
In2011,threepaperswerepublishedbytheERIgroupdemon-stratingthatwithonlyarelativelyminorchangetothe"tail"ofthemolecule(l"Fig.
4),significantpharmacologicaleffectscouldbedemonstrated.
Ifthediolthatistheeribulinprecursorwaschangedtothedimethoxysubstituent,ortheterminalaminogroupwaschangedtoamethoxygroup,thecompoundsnowhadamuchlowerpropensityforinducingP-glycoproteinsuscep-tibility.
Bothcompoundswerepotentinvivoandhadareductionofapproximately30-foldintermsofbeingsubstratesforP-glyco-proteincomparedtoeribulin[78].
TheERIchemiststhendemonstratedthatbysubstitutingasub-stituted1,4-diazacyclohexanylgroupfortheterminalaminogroupineribulinandchangingthesidechainhydroxylgrouptoamethoxyl,thecompound(l"Fig.
4)demonstratedoralactivityinasubcutaneousLOXmelanomamodelandmaintainedalowsusceptibilitytoP-glycoproteininduction[79].
Sincethereareveryfewtreatmentsforbraintumors,thegroupthenmodifiedthebaseeribulinmoleculebyringclosureatthe"tail"togiveamorpholinoderivative(l"Fig.
4).
Thismoleculewassubtlydiffer-entfromtheorallyactivecompoundreferredtoabove,anddem-onstratedintravenousinvivoactivityinanorthotopicmurinemodelofahumanglioblastoma[80].
Althoughittook25yearsfromtheoriginalreportin1985onhal-ichondrinBuntillate2010toapproveeribulin,theinterplayofacademic,industrial,andgovernmentlaboratoriesinthreeconti-nentsledtothisnovelagent,themostcomplexdrugmoleculeyetproducedbytotalsynthesis.
WhatisofgreatimportanceisthatwithoutthestructureofthehalichondrinBfromaJapanesespongeandthesubsequentpurificationofhalichondrinBbyNZscientistsandtheNCI,eribulinwouldnothavebeenapproved,norwouldtheveryinterestingandnovelagentsreferredtointheprecedingparagraphhavebeensynthesized.
Ziconotide:ConeSnailToxinsasPainTreatment!
ThefundamentalworkbyOliveraetal.
onthepeptidicneurotox-insfromfish-huntingconesnailsledoverthenext20orsoyearstoamassiveamountofinformationonthesources,theutilityinboththesnail,andthepotentialforuseorleadstoadrugofuseinman[81].
WhenitwasrealizedbyOliveraandhiscolleaguesthatthesepeptidictoxinswereveryspecificastowhichofthecation-gatingchannelstheyinhibitedand/oractivated,thenthestudyofthesepotentialneurologicalagentsbeganinearnest[82].
AsaresultofOliverasworkattheUniversityofUtah,asmallcompany(Neurex)wassetuptoevaluatethe25-mercyclicpep-tide,nowknownasziconotide(l"Fig.
5),thatwasoneofthemanypeptidictoxinsfoundinConusmagus.
Closeto200modifi-cationsofthetricyclicpeptide(threeCYSCYSlinkagesbeingthemajorstructuralmotif)weresynthesizedandevaluatedfortheirpharmaceuticalpotentialbutintheend,thenaturalproductwasthechoice,eventhoughmadesynthetically[83].
Thiscompound(ziconotideorPrialt;l"Fig.
5)subsequentlybe-camethefirstmarine-derivedproducttogainapprovalasadrugonitsapprovalbytheFDAonthe28thofDecember2004,thoughitpassedthroughanumberofcompaniesenroute,followedrap-idlybyapprovalintheEUbytheEMEAtwomonthslater.
Zicono-tide,thougheffectiveinitslimitedapplication,isnotadrugthatistakeneasilyasithastobedeliveredviaanintrathecalinjectionroute.
XEN-2174(PhaseII)Thiscompoundisaveryslightmodificationofthenaturallyoc-curringχ-conotoxinMrIA.
ThatcompoundwasoriginallyisolatedfromC.
marmoreusandthenoptimizedbymedicinalchemistry[84].
Unliketheotherconotoxins,eitherapprovedorinvariouslevelsoftesting,thisparticularagentisa13-residuepeptideandisanoncompetitiveinhibitoroftheneuronalnorepinephrinetransporter(NET)[85].
Fig.
5Conesnailtoxins.
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Thesourcecompany,Xenome,isstilllistedonvarioussitesashavingthiscompoundinPhaseIItrialsagainstcancerpain,andinanabrogatedtrialatPhaseIIcounteringpainfrombunionsur-geryinBulgariaundertheEudraCTprotocol010–019109-40-BG.
ThislattertrialwasterminatedbytheFDA,butnodatahasyetbeenpublished.
However,asearchoftheinternetundertakeninAugust10th2015,showsthatthewebsite"www.
xenome.
com"isupforsale,thusthecurrentstatusofthiscompoundisun-known,butfullerdetailsofthedevelopmentofthiscompoundandofPrialtwerepublished(February2015)inabookchapterthatcanbeconsultedforfurtherinformation[86].
Duetotheun-certaintyastotheactualstatuscommentedonabove,wehaveusedthe"PhaseII"headingforthissection.
Leconotide(ω-ConotoxinCVID;PhaseI)Thismolecule,a27residuepeptidewiththreeinternalCYSCYSbonds,similarinoverallstructuretoziconotide,hadreachedPhaseItrialssponsoredbyRelevarePharmaceuticals(Australia;previousnamewasCNSBio)fortreatmentofpainrelatedtocan-cer.
ItisacalciumchannelblockerandwasoriginallyidentifiedbyresearchersattheUniversityofQueensland.
Althoughinitialexperimentsusedtheintrathecalroute(aswithziconotide)[87],theprotocolusedsystemicadministration[88].
Thecom-panyinvolvedhasnowliquidated,sojustaswithXEN-2174,thecurrentstatusisunknown.
Recently,CraikandcoworkersinAustraliahavedemonstratedthatbytakingstructuralcuesfromplantcyclotides,theycanalterthepeptides(includingconesnailtoxins)pharmacologicalchar-acteristics,producingoralanalgesicactivityinanimaltests,thusopeningupothermethodsofdelivery,avoidingtheverydifficultcurrentintrathecalroute[89,90].
Asmentionedabove,arecentbookhaschapterswrittenbytheexpertsinthisfieldandwerecommendthatinterestedreadersconsultthechapterswritteninconjunctionwithOlivera[91]andAlewood[92]formuchmorebackgroundinformationontheseveryinterestingnaturalproductsandderivatives.
UnapprovedMarine-SourcedCompoundsinCurrentClinicalTrials!
Thereareanumberofmarine-derivedagentsthathavebeenintrialsupthroughPhaseIIbutforonereasonoranother,havenotbeencontinued.
Somewerefortoxicity,someforlackofefficacy,butthesearenotdiscussedanyfurther.
However,inatleastonecase,thatofahemiasterlinderivativeHTI-286ortaltobulin,thecompound,thoughheadedforPhaseII,wasdiscontinuedfor"businessreasons"byWyeth.
Thehistoryofthatparticularcom-poundwaspresentedbyAndersenetal.
in2012[93].
However,thecompoundsdiscussedinthissectionarethosethatarenot"descendedfromorrelatedto"thosethatarecurrentlyapproved,butareallinclinicaltrialsatthetimeofthiswriting,orinsomecases,thetrial(s)has/havebeencompleted,butnode-tailshaveyetbeenpublished.
Theyaredividedbythedisease(s)forwhichtheyareunderdevelopment.
Analgesia:tetrodotoxin(PhaseII/III)Asidefromtheconotoxins,perhapsthemostunusualagentatthisstageisaverywell-known"marinetoxin",thehighlysubsti-tutedguanidine-derivativetetrodotoxin(l"Fig.
6)[94–96].
WEXPharmaceuticalshasplacedthecompoundintotwoPhaseIIItri-alsintheUSAasanagent(Tectin)againstinadequatelycon-trolledpainrelatedtocancer(NCT00725114;00726011).
One(NCT01655823),againintheUSA,wasterminatedunderthesamecompanyatPhaseII(againstneuropathicpainresultingfromchemotherapy-inducedperipheralneuropathy),becausetheinterimresultsweresuchthattheywishedtomovedirectlytoaPhaseIIItrialforthesameindication.
Althoughtherewasdebateinyearsgonebyovertheactualsourceofthisagent,thereisnowlittledoubtthatitisproducedbyacommensalmicrobe,thoughwhichone(s)is/arestillopenfordebate[97].
Thesynthesisofthecompoundandotherderiva-tiveshasbeenpublishedfromavarietyofchemists,withanex-cellentreviewbyNishikawaandIsobein2013[98],givingthehighlightsoftheirmethodologiesandcoveringsomeoftheearlyhistoryofthisclassoftoxins.
Thispapershoudbereadincon-junctionwiththemorecomprehensivereviewonthebiologyandchemistryoftetrodotoxinbyBaneetal.
,wheretheyevenmentionthe25plusvariationsonthebasicstructuresofarre-ported[99].
PET-Imaging18F-SaxitoxinForcomparison,anotheralgal/cyanophyte/bacterialproductcloselyrelatedtotetrodotoxinisbeingconsideredforinvivoPETMRimagingofvoltage-gatedsodiumchannels;inthiscase,18F-saxitoxin(l"Fig.
6)[100].
Saxitoxinhasbeenwelldescribedwithanexcellentreviewin2014,sothisagentmaywellendupnotonlyasacuriositybutasavaluableagentfrommarinesour-ces,thoughwhetheraformalclinicaltrialwilloccurisnotcertain[101].
AntitumorCompounds!
Aplidine(Plitidepsin,PhaseII/III)Aplidine,whichisformallydehydrodidemninB(l"Fig.
6),isaveryclosechemicalrelativeofthefirstdirect-from-the-seaanti-tumorcompounddidemninB(l"Fig.
6).
ThelattercompoundwenttoPhaseIItrials,butwasterminatedduetotoxicityprob-lems,possiblyduetothemethod(s)ofdelivery,assuggestedbyVeraandJouille[102].
AplidinewasoriginallyisolatedfromApli-diumalbicansandfirstreportedinapatentapplicationin1989,Fig.
6Unapprovedmarine-sourcedcompoundsincurrentclinicaltrials.
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withaUKpatentissuedin1990.
ItwasformallyidentifiedinthechemicalliteratureinapaperfromRinehartsgroupin1996cov-eringthestructure-activityrelationshipsamongstthedidemnins[103].
Theearlierworkonaplidine,itsentryintoPhaseIandIItrials,andthepreferredmethodofsynthesiswasdescribedinde-tailthroughlate2004byPharmaMarscientists[104],withfur-therinformationthroughlate2011byPharmaMarscientistsinthesecondeditionin2012ofthe2005book[46].
Currently,thisagentislistedinfourclinicaltrialsbycross-refer-encingagainstthethreeclinicaldatabases,oneatPhaseIII,twoatPhaseII,andonePhaseI.
IntheEudraCTclinicaltrialsdatabase,onePhaseIIItrial(2009–016138–29)islistedinmultiplemyelo-ma.
ThisisalsolistedintheNCIclinicaltrialsdatabaseasNCT01102426,aPhaseIIItrialwithorwithoutdexamethasoneagainstresistantmultiplemyeloma,theADMYREtrial.
ThereisadifferenceintheNIHandtheEUdatabaseswithrespecttoaPhaseIItrialagainstliposarcoma,wherethetrial(2009–010980–18)intheEUdatabaseislistedasongoinginFrance,theNIHtrial(NCT01876043)islistedasbeingterminatedinearly2015,whichagreeswiththeWHOdata.
However,sincetheWHOlistingispopulatedbytheNIHdata,thereisstillsomeconfusionastothestatus.
TheEUdatabasestillhasanopenPhaseIItrialinSpainunder2004–001117–34againstrelapsedorrefractorynon-Hodgkinslymphoma,whereastheNIHdatabaseshowsthatthetrial(NCT00884286)hasbeencompleted.
ThereisonePhaseItrial(NCT02100657)recruitingatthePhaseIlevelformultiplemyelo-mathatcommencedinthemiddleof2014.
ThisisnotshownintheEUdatabase,butisintheWHOone,thoughprobablypopu-latedfromtheNIHdatabase.
ThepreciseMOAofthisagentinatumorenvironmentisnotfullydescribed,butin2009,Munoz-Alonsoetal.
describedsomeofthethenknowncellularinteractions[105],andin2014,scien-tistsworkingwithPharmaMardescribedthefurtherinteractionswithelementsoftheimmunesystem[106].
Thispapershouldbeconsultedforfurtherspecificinteractions.
InabstractspresentedattheEORTCconferenceinNovember2014,PharmaMarscien-tistsandcolleaguesreportedthataplidinbounddirectlytotheeukaryoticelongationfactor1A2(eEF1A2),atargetthatisover-expressedinmultiplemyeloma(MM)andacutelymphoblasticleukemia(ALL)[107,108].
Formoreinformationonthesepath-ways,thetworecentreviewsfromthePelletiergroupatMcGillUniversityshouldbeconsulted[109,110].
PM050489/PM060184(PhaseI)Thisagent,apolyketideanditschloroderivative(PM050489),wasisolatedfromtheMadagascanspongeLithoplocamialithis-toides,withtheextractdemonstratingantimitoticactivityandtheisolatedagents,tubulin-bindingactivities.
Duetothelowlev-eloftheseagentsinthesponge,synthesesweredescribedbythePharmaMargroup[111]in2013.
Thisinitialpaperwasfollowedthesameyearwithevidenceforbindingatorclosetothevincadomain[112].
In2014,furtherevidenceofactivityofthedes-chloroderivative(PM060184,l"Fig.
6)againstP-glycoprotein-expressingtumorswaspublished[113].
Currently,PM060184(l"Fig.
6)isinonelistedPhaseItrialintheNIHdatabase(NCT01299636)thatcommencedinSanAntonio,Texasin2011,withthesametriallistedintheWHOdatabaseandnolistingsintheEUdatabase.
ItislistedinPhaseIinthePharmaMarpipeline(accessedAugust8th,2015)andatthe2014EORTECMeeting,therewasaninterestingreportofinvivoactivityinmiceatlowlevelsofthisagent[114].
AlsoattheEORTEC2014meeting,therewasaveryinterestingreportfromPharmaMarshowingthatthechloro-derivative(PM050489)couldbelinkedtotrastuzumabbyreductionoftheantibodywithaphosphinereagent,couplingtoamaleimidode-rivativeofPM050489,followedbypurificationbysizeexclusionchromatographytoyieldtheresultingconjugate(MI130004)[114].
ThisADCshowedinvitroactivitywhentestedagainstcelllineswithselectivitytowardscelllineswithhighHER2expres-sion(IC50s0.
282and0.
182nMagainstHCC-1954andSKBR3celllines,respectively),whilstHER2nullcellswereunaffectedintherangeofconcentrationstested(upto300nM).
Invivo,MI130004alsodemonstratedefficiencyincausinganoutstand-ingtumorreduction,withcompleteregressionsinmostoftheanimalsthatreceivedthetreatment[115].
Pipecolidepsin,stellatolideA,andirvalecThePharmaMargrouprecentlypresenteddataatthe2014EORTECmeetingthatdemonstratedactivityinthesethreemodi-fiedmarine-derivedcompounds(l"Fig.
7)[51,116,117].
IrvalecwaspulledfromclinicaltrialsbyPharmaMaratthePhaseIIlevel,soitisinterestingthattheyarenowreportingonitandtheothertwo[118].
Marizomib(SalinosporamideA;NPI-0052;PhaseII/I)ThestoryofthiscompoundfromitsdiscoveryfromthemarineactinomyceteSalinisporatropicaanditsidentificationasapro-teasomeinhibitorhasbeencoveredextensivelyinthescientificliterature.
ThesereportsincludeaworkuptogivethecGMPprod-uctfromthefirstmarinemedium-basedlarge-scalefermenta-tionthroughsynthesisbyavarietyofchemistsbothinacademiaandcompanies,andidentificationofthebiosyntheticclusterinFig.
7Pipecolidepsin,stellatolideA,irvalec,salinosporamideA.
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theproducingorganism(s)[119–122].
Thesewerefollowedin2014byanexcellentarticlebyJensenetal.
givinguptodatein-formationonthegeneticanalysesoftheproducingorganismandothersfromthesamegenus[123].
Thenlaterthesameyear,therewasareportofthefirstdiscoveryofthegeneclusterforsalino-sporamideAinSalinisporaarenicola(ratherthanS.
tropica)col-lectedintemperatewatersbyGooetal.
[124].
NereusPharmaceuticals,thecompanysetuptodevelopthiscompoundandothersfromJensen/Fenicallaboratories,liq-uidatedtwoorsoyearsagoandallIP,etc.
,weretransferredtoTri-phaseResearchandDevelopmentCorporation.
Currently,intheNIHdatabase,therearetwoPhaseItrials"recruiting"(NCT02330562and02103335),bothcommencingin2014,plusaPhase1/IItrialinmultiplemyelomalistedas"activebutnotre-cruiting"(NCT00461045).
Thislattertrialstartedin2007underNereusandfrom2013,waslistedunderTriphase.
Thisdataisintheclinicaltrialsarchivelisting,accessiblefromtheregularNIHclinicaltrialswebsite.
AlzheimersDiseaseandAntiviralCompounds!
Bryostatin1(PhaseII,AlzheimersDisease)Theisolationofthefirstofthis20-membered(now21plusvideinfra)classofmacrolidiccytotoxinsfromthefoulinginvertebrateBugulaneritinaover30yearsagoledtomassivecollectionsofthenominalproducingorganismandtoveryelegantsynthesesofvariouscomponents.
Theinitialdiscoveryofbryostatin3(l"Fig.
8)wasindirectlyreportedin1970,thesubsequentdevel-opmentsleadingtothereportoftheisolationandXraystruc-tureofbryostatin1(l"Fig.
8)in1982,togetherwiththemulti-yearprogramthatculminatedintheisolationandpurificationof18bryostatins,havebeenwelldocumented[125].
Alloftheknownbryostatinspossessa20-memberedmacrolac-toneringwiththreeremotelysubstitutedpyranringslinkedbyamethylenebridgeandan(E)-disubstitutedalkene;allhavegeminaldimethylsatC8andC18,andafourcarbonsidechain(carbons4–1)fromtheAringtothelactoneoxygen,withanotherfourcarbonchain(carbons24–27)ontheothersideofthelac-toneoxygentotheCring.
MosthaveanexocyclicmethylenoateintheirBandCrings,thoughbryostatin3,inparticular,hasabu-tenolideratherthantheCringmethylenoate,andbryostatins16and17haveglycalsinplaceoftheregularC19andC20hydroxylmoieties[125,126].
WorkreportedfromthePeoplesRepublicofChinain1998[127]andin2004[128]gavethestructureforbryostatin19purifiedfromaSouthChinaSeacollectionofBugulaneritina.
Then,inthesameyear,thisreportwasfollowedbythepublicationbyLo-paniketal.
reportingtheisolationofbryostatin20fromanAtlan-tic-sourcedB.
neritina[129].
Comparisonwiththestructuresoftheother18bryostatinsshowsthatthesearecloselyrelatedtobryostatin3intermsoftheirbasicringcomponents.
Veryre-cently,theChinesegrouppublishedthestructureofbryostatin21andalsofourderivativesofknownbryostatins[130],sotherearenow21to25naturallyoccurringbryostatins.
Thesubstitutedbryostatins22–25couldbeartifactsoftheisolationtechniquesused,sountilfurtherconfirmationisobtained,wewilluse21bryostatinstodate.
Bryostatin1hasbeenthroughwellover80PhaseIandPhaseIIclinicaltrials,withorwithouttheadditionofacytotoxicagentintheprotocols,butinnocasehasthecompoundprogressed.
Insomeoftheearliertrials,themodeofdelivery(abolusatorclosetothemaximumtolerateddoseorMTD)mayhavebeenthema-jorproblem,asmyalgiawasaserioussideeffect.
In2011,theKeckgroupreportedthefirstcompletetotalsynthe-sisofbryostatin1[131],whichwasrapidlyfollowedbyapaperfromManaviazarandHalewithdetailsofashorterroutetothesamecompound[132].
Laterthesameyear,Trostetal.
publishedpapersonthering-expandedversionsofbryostatinsobtainedbytotalsynthesis,sothesyntheticstoryofthisclassofmacrocycleshasnotyetfinished[133,134].
Itisnowalmostcertainthatbryostatinsareproducedbyanasyetunculturedmicrobefoundinitiallyinthelarvaeofthebryozoan.
CurrentinformationcanbeobtainedbyinspectionofthereviewbytheHaygoodgrouppublishedin2010[135].
Whatisofcurrentimportance,however,isthereportbyNeuro-tropethatthePhaseIIastudy(NCT02221947)ofbryostatin1inAlzheimersdisease,whichwasterminatedandreplacedbythetriallistedbelow,demonstratedthatbryostatin1couldbedeliveredsafelytopatients.
Thefollow-onPhaseIItrial(NCT02431468)islistedas"notyetrecruiting",effectivethemiddleofApril2015withNeurotropeInc.
(andisstilllistedthesamewayinlateNovember2015);thisisincontrasttotheearliertriallistedforthesameindicationbutwithnoinforma-tionpostedsince2008(NCT00606164)underadifferentspon-sor.
Bryostatin1and"Latent"HIVAnumberofsimplifiedbryostatinanalogues(oftencalled"bryo-logs")havebeensynthesizedusingmethodssuchasfunction-orientedsynthesis.
ThistechniquewasemployedbyWenderandotherworkerstodevelopsimplifiedanalogueswithcompa-rableormuchimprovedactivities,insomecasesordersofmag-nitudeininvitroassays[136–138].
Furtherinformationwasgiv-eninareviewbyNewman[139]andinarecent2013paperbytheKeckgroup[140].
WhatisalsoofsignificantimportanceistherecentreportbytheWendergroupofinvitroanti-HIVactiv-ityforsomeoftheirneweranalogues[141].
InJune2015,AphiosInc.
inMassachusettsannouncedthattheyhadenrolledpatientsforaPhaseI/IIstudyofbryostatin1inatri-althatisdesignedto"release"theHIVvirionsfromtheirlatentsitesinpatients.
Thisisawell-knownphenomenonofanumberofvirusesincludingHIV,andisthebasisoftheanti-HIVtreat-mentknownasHAART(highlyactiveantiretroviraltherapy).
ThesetrialsarebeingconductedinSpain,withaPhaseIrecordunderNCT02269605.
Bryostatin1wasproducedusingAphiosnowpatentedsupercriticalfluidtechnique,whichwasused,thoughnotundercGMPconditions,asacomparatormanyyearsagoinbryostatin1purificationprocesses[142].
Fig.
8Alzheimersdiseaseandantiviralcompounds.
784NewmanDJandCraggGM.
DrugsandDrug…PlantaMed2016;82:775–789ReviewsThisdocumentwasdownloadedforpersonaluseonly.
Unauthorizeddistributionisstrictlyprohibited.
Thoughbryologshavenowyetbeentried,ifthesetrialsaresuc-cessful,thenitisfeasiblethatoneormoreoftheWenderorKeckcompoundscouldbeacandidatefortrialsagainstHIVorothervi-rusesthatexhibitlatency,suchastheherpessimplexcomplex.
Griffithsin(MicrobialVirucideHeadedforClinicalTrials)This121-residuepeptidicagentwasfirstreportedin2005fol-lowingitsisolationfromtheredalgaGriffithsiasp.
Duetosourceconstraints,itwassubsequentlyproducedbytransferoftheDNAsequencecorrespondingtothepeptideviaaplasmidinto,andsubsequentexpressionin,Escherichiacoli[143].
Thematerial,ei-thernaturalorrecombinant,wasultimatelyshowntobindtospecificmannose-richregionsofHIVviralproteins[144].
In2009,itwasreportedthatthecompoundcouldfunctionasatop-icalmicrobicidewithpotentialasanintra-vaginalagenttopro-tectagainstHIVtransmission[145].
Sincethatpublication,workhascontinuedwiththiscompoundbydemonstratinglarge-scaleproductioninplants[145],furtherefficacy[146],andtoxicitystudiesinrodentmodels[147].
Currently,thePopulationCouncilisdevelopingagriffithsin-con-tainingmicrobicidetopreventthetransmissionofHIVandothersexuallytransmittedinfections(http://www.
popcouncil.
org/research/developing-and-testing-a-griffithsin-non-arv-microbi-cide).
Thatwebsitehasthefollowingstatement:"In2013,theCouncilwasawardedacooperativeagreementfromPEPFAR,andadministeredbyUSAID,toinvestigategriffithsin(GRFT)asavaginalmicrobicide.
GRFTisanaturallyoccurringproteiniso-latedfromalgaethathaspotentactivityagainstHIVandotherSTIs.
GRFTfordrugdevelopmentisproducedintobaccoplants,andinitialpre-clinicaltestinghasshownittobesafeandnon-irritatinginvitro(incellsandtissue)andinvivo(inanimals).
CouncilresearchersaredevelopingaGRFT-containingmicrobi-cidegelforpre-clinicalandclinicalstudies.
Resultsfromthesestudieswillinformthedevelopmentofotherdeliverysystems,includinganintravaginalringtoprovideprotectionimmediatelyandupto90days.
"(accessedAugust17th,2015).
InConclusion!
Inthisreview,weinitiallyconcentratedonmaterialsthatareap-provedasdrugsbytherelevantauthorities.
Inaddition,wehavediscussedcompoundsthatarechemicallyrelatedtothoseap-proveddrugs,andthencompoundsthatareinclinicaltrialsmainlyagainstcancer,butalsoAlzheimersdiseaseandHIV.
Theemphasisoncancerissimplyduetothefactthatthemajorfund-ingagencyformarine-derivedcompoundsformanyyearswastheNIH/NCI,andtosomeextent,thiscarriedoverinothercoun-tries.
Therearealargenumberofveryinterestingcompoundsthathavebeenisolated,usuallyviaactivity-drivenisolationprocessesfromsingle-celledorganisms,inparticularthecyanobacteria.
Therearesomeexcellentcurrentreviewscoveringcompoundsfromthesephotosyntheticbacteriathathavebioactivitiesrang-ingfromantitumortoneurologicaldiseases,butnonehaveyetmadeittoclinicaltrials[148–150].
Whatisnoticeable,however,isthatnoantimicrobialcompoundsfrommarinesourceshaveyetmadeitbeyondthediscoveryphaseintowhatisknowninthepharmaceuticalindustryas"thepreclinicalphase".
Thismaywellbeafunctionofthecurrentlackofantimicrobialresearchinthemajorpharmaceuticalcompanies(whichusedtobeamajorsourceofnaturalproduct-basedcompounds),coupledtoalackoffundinginthisareaforbothdiscoveryand,particularly,devel-opment.
However,averyrecentreviewbyNgetal.
demonstratesthattherearedefinitelypossibilitiesinthesediseaseareasformarine-sourcedcompounds[151].
Finally,weconsiderthatthepotentialformarine-basedcom-poundsinalldiseaseareasisimmense.
Whenonerealizesthatcurrentlythereareapproximately25000definedchemicalcom-poundsreportedtodatefrommarinesources,andtherearesevenapproveddrugs[(includingtheomaga-3-acidethylestersandvi-darabinenotdiscussedinthisarticle[152],andonemayalsocheckthewebsiteofProfessorA.
M.
S.
MayerintheUSA(http://marinepharmacology.
midwestern.
edu/clinPipeline.
htm)forthesesour-ces(directormodifiedstructures)],thenasuccessratioof1in3500isordersofmagnitudebetterthosefromsyntheticmole-cules.
ConflictofInterest!
Bothauthorsdeclarethattherearenoconflictsofinterestwiththecontentofthismanuscript.
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