2Itisacombinationofsimpleandeasilyavailablestructuralfragments
HuatengPharma https://ushuatengscicom Non-internalizedADCApplications
Whatarethecharacteristicsof"clickchemistry"?
4Productseparationprocessissimple,noneedtousechromatographyfor separation.
"ClickChemistry"HoldsPromiseFor
Whatis"ClickChemistry"?
5Thereactioncanbecarriedoutinwaterandorganicsolvents Examplesofearlyapplicationsof"clickchemistry"
canbeperformedinlivingsystemswithout interferingwithnormallifeactivities.Overthepasttwodecades,bioinorganic andmedicinalchemistshaveincreasinglyusedthischemicalapproach, especiallyinthedevelopmentoftargeteddrugs,suchasantibodydrug conjugates(ADCs)
Theterm"clickchemistry"wasfirstcoinedbyProfessorK.B.Sharplessofthe ScrippsResearchInstitute(2001NobelLaureateinChemistry)Itisaclassof reactionsinvolvingtheformationofcarbon-heteroatombonds,whichare characterizedbyhighyieldandselectivity
Bioorthogonalclickchemistry
3.Almostnoby-productsaregenerated.
1.Thechemicalyieldofthetargetproductisveryhigh.
Clickchemistrywasfirstusedfortracing,becausesomeinvitromethodsof labellingreinjectionarenotfullyeffectiveandmayalsocauserejection. Inthefigurebelow,ifwewanttostudythedistributionandchangesofSiaNAz (asugaronthesurfaceofcells)invivo,weneedtotraceitTheoperationof clickchemistryisasfollows:Ac4ManNAzcanbeconvertedintoSiaNAzin vivoTheresearchersaddedanN3group(azidegroup)totheformer,and theninjectedAC4MannaZN3intomice.Afewdayslater,themicewere injectedwithaFLAGlabeledmolecule,whichcarriedagroupthatcouldreact withN3group(alkynylgroup).WhenthemoleculemetSiaNAzintheprocess ofmetabolisminvivo,itwill"click"likethebuckleofasafetybelt,andthe FLAGwillbecarriedtooursugarmoleculesbychemicalreactions,thus achievingtheeffectoftracing(andbecauseN3issosmall,itwon'taffectthe bioconversionprocessofsugarmolecules).
Source:NatBiotechnol.2019Aug;37(8):835-837.
ApplicationofclickchemistryinADCfield
HuatengPharma https://ushuatengscicom
1.Cleavageofnon-internalizedADCsbyclickchemistry
Source:CarolynRBertozzietal
isstillintheclinical stage,andtherearenotmanyresearchanddevelopmentcompaniesIt belongstoanemergingfield,butaccordingtothecurrentefficacy,itisvery worthexploring BiotechcompaniesthatusebioorthogonalclickchemistrytoprepareADCs
Copperfreeclickchemistryinlivinganimals,PNAS,2010,5,18211826
TheapplicationofclickchemistryinthefieldofADC
HuatengPharma https://ushuatengscicom TagworksPharmaceuticalsisdevelopingabioorthogonalclickchemistry strategytoovercomesomeoftheshortcomingsofADCsintargetingsolid tumorsTraditionalantibodydrugconjugates(ADCs)targetinternalized receptorsoncancercells,resultingindrugreleasebyintracellularcleavageof linkers.However,onlyasubsetofpatientswithsolidtumorshaveadequate expressionofspecificinternalizingreceptors
TagworksPharmaceuticalsusesclickchemistrytocleavenoninternalized ADCs 2.Tagworks:AChemically-cleavableADCforTAG72Targets Tumor-associatedglycoprotein72(TAG72)isanoninternalizedtargetthat iswidelyexpressedinarangeofhumanadenocarcinomasofepithelialorigin, suchasbreast,colorectal,gastric,lung,pancreatic,prostate,andovarian cancers.Tagworksisdevelopingclick-cleavableanti-TAG72ADCsbasedon antibodyfragmenttypes,conjugatedtotheantimitoticagentMMAE
Basedonthis,TagworksPharmaceuticalshasdeveloped aClick-to-Releaseapproachtomakenon-internalizedtargetsapplicableto ADCtherapeutics:ADCtargetsnoninternalizedreceptors,whichcontaina connectorthatcanonlybedestroyedbybioorthogonalchemicalclickreaction. WhentheADCisenrichedaroundtumorcells,systemicadministrationof anactivatorreactswiththeADClinkeroutsidethetumorcell,resultingindrug releaseinthetumormicroenvironmentandsubsequentuptakeinto surroundingcancercellsandtumor-supportingstromalcellsforaction. ADCscleavedbyclickchemistryhaveexpandedtheiruse,enabling pervasiveanddirecttemporalcontrolofdrugreleaseinthetumor microenvironmentThiswouldallowformoreuniformdrugdelivery,potentially improvingthetherapeuticeffectofheterogeneousorpoorlypenetrating tumors
HuatengPharma https://ushuatengscicom
Shasqi,fromSanFrancisco,California,isalsoworkingonbioorthogonal chemicalclickreactionsinpatientswiththeClickActivatedProtodrugs AgainstCancer(CAPAC™)platform,awaytoactivatecancerdrugsatthe tumorsiteandreducesystemictoxicityShasqiisclinicallyvalidatingthe efficacyofitsplatformbyusingSQ3370,whichalsomarksthefirsttimethat clickchemistryhasbeenperformedinapatient
3.ShasqiBio:CAPAC™Platform--SQ3370(ClickActivatedProtodrugs AgainstCancer)
Theresearcherslocallyinjectedanalginatehydrogelmodifiedwithachemical clickhandle(tetrazine)atthetumorsite,followedbyintravenousinjectionofa prodrugwithacomplementaryhandle(forexample, transcyclooctenemodifieddoxorubicin).Theprodrugisstableinvivoandhas littleactivityuntilitismetabolicallycontactedwiththehydrogel,atwhichpoint achemicalclickreactionoccurs,therebyreleasingthedrugThisreduces offtargetexposureandenablesveryhighlocaldosesofthedrug.
"ChemicallycleavableADC+activator"hassignificantefficacyandlong survival
Theactivatorisadministered13dayslater,therebyrapidlyreleasingMMAEin thetumormicroenvironmentandspreadingintosurroundingtumorcells, maximizingthebystandereffect AdualantibodybasedantiTAG72ADCshowedpotentantitumorefficacyin micewithcolorectalandovariancancerxenograftswithoutdetectabletoxicity. Incontrast,similarADCcontrolswithvalinecitrullinelinkerwerelesseffective inthesemodels.
HuatengPharma https://ushuatengscicom
Source:ACSCentSci.2016Jul27;2(7):47682.
Therapeuticeffectofdoxorubicinprodruginsofttissuesarcomaxenograft model
Aftertreatmentmonitoringinthexenograftmodelover100days,themedian tumorsizeofthedoxorubicinprodrugcohortremainedunchangedandboth wereundetectable(P=0021),whilethecontrolgroupreboundedrapidlyat day50.Atthesametime,thebodyweightofthedoxorubicinprodruggroup hasbeenatastablelevel,whilethebodyweightofthecontrolgroupmicehas beendecliningwiththetreatmenttime.
ClickActivatedProtodrugsAgainstCancer(CAPAC™)platform
[4]Invivobioorthogonalchemistryenableslocalhydrogelandsystemic prodrugtotreatsofttissuesarcoma
“ClickChemistry"hasmanydifferentformsofapplicationinthefieldof ADCs,allofwhicharehighlyeffectiveandareatanearlystageofresearch, anditreliesonreactionsthatcanoperateintheorganismwithoutdisrupting biochemicalprocesses,andhasawideapplicationpotential HuatengPharmaisaleadingCDMOforPEGderivativesandpharmaceutical intermediateswhichcanmeetcustomers’needsfromlabresearchtopilot planttolargesaclecommercialproduction.WesupplyavarietyofPEG reagentsforclickchemistryreaction
Conclusion
References: [1]Clickchemistrytargetsantibody-drugconjugatesfortheclinic [2]Copperfreeclickchemistryinlivinganimals
Relatedarticles: [1]AntibodyDrugConjugatesforCancerTherapyProspectsandChallenges
[2]ADCLinkerDevelopmentandChallenges
HuatengPharma https://ushuatengscicom
[3].InVivoBioorthogonalChemistryEnablesLocalHydrogelandSystemic ProDrugToTreatSoftTissueSarcoma