PhD Proposal in Cancer Research sample

[Pages:3]PhD Proposal in Cancer Research sample

ProjectDetails

Proposed Title:Creation and synthesis of bifunctionaldegraderlibraries forthe discovery of possible cancer targets.

BackgroundoftheProject

Thesuccessofthetargetdiscoveryofcancerdrug ishighlydependenton the determinationofproteintargetswhichcanbemodulatedusingsmallmolecules,thus producinganti-cancereffects.Thepurposeofthisprojectistopossiblyapplytheuseof syntheticorganicchemistry,combinedwithmedicinalchemistrytothecreationand synthesisofalibraryofdifferentcompoundswhichcanpromoteproteindegradation. After,thesewillbeusedinidentifyingproteintargetswhichwillthenbeusedinthe discovery of new cancer drugs.

BifunctionaldegradesareanewlydiscoveredmoleculeclasswhereinanE3ubiquitin ligasebindingcompoundisconnectedtoawarheadwhichbindsitstherapeutictarget.In contrastwithotherconventionalsmallermoleculedrugswhichbindandblocksthe action oftheirprotein targets,thesebifuncitonaldegradersworkbycatalyzing the formulationofacomplexinbetweenanE3ligase,aswellasatargetprotein,thus allowingforubiquitination,thusresultingtotheirreversibleandrapiddegradationofthe potentialtarget.

Thisconceptwillbeappliedtotargetfinding,bycreatingandsynthesizinglibrariesof bifunctionaldegraders,screeningthem usingassaysinthecellularlevel.Theprocessof chemoproteomicswillbeusedinordertoidentifythetargetswhichwillbedegraded. Theprimarybenefitsofthisapproachintargetidentificationincludetheunderstanding thatidentifiedtargetsaredruggable,hittingcompoundswhichhavethepotentialto effectivelyrepresentcellularprobes,thusservingasstartingpointsforchemistry.

Thestudentwhowillbeconductingthisresearchwillbegivensupportbya supervisoryteam withbothindustrialandacademicexpertiseinbothmedicinaland syntheticchemistry,chemoproteomicsandcancerbiology.Thestudentwillalsobe mainlyplacedinthe4thGroupoftheMedicinalChemistryteam,alongwithDr.Strauss Meyer.Thecandidatewillalsobeprovidedwiththeopportunitytospendsometimewith theMolecularTherapeuticsteam andTargetEvaluationgroup.

AimsoftheProject

Overallpurpose:

Tocreateanewtargetidentificationmethodwhichexploresthedifferentlibrariesof bifunctionaldegraderswhilepresentingsomeproofofconcept.

Steps required:

Discoveranddeveloptherightsyntheticroutestoallowforthepreparationof differentbifunctionaldegraders.

Usevariousphysicochemicalproperties,aswellasexpertiseinthefieldofmedicinal chemistryinordertoallowforthedesignofbifunctionaldegraderswhichcrossescell membranes.

Synthesizevalidationsetsofdifferentcompounds,whichwillthenbefollowedbythe preparationof200-compounddegraderlibrary.

Testcompoundsusingaseriesofcellularassays,alongwiththedevelopmentand theapplicationofdifferentchemoproteomicmethodsinordertoidentifydifferent targets.

Research Proposal

Syntheticroutesdevelopmenttobifunctionaldegraderlibraries

Duringtheproject'sinitialphase,thestudentwillworkonapplyingsyntheticroutes, combinedwithsomein-houseexpertiseinordertopreparedegraderswhichwillbeused duringtheinitialvalidation.Thedevelopmentofneworalteredsyntheticrouteswillbe undertaken,soastoestablishtheparallelsynthesisforbiggercompoundsets.Thiswill allowthecandidatetostartontheircurrentpracticalandtheoreticalknowledgeor organicsynthesis,whiledevelopingskillsinpurificationandparallelsynthesis.Allof thesewillbedoneundertheguidanceofexperiencedsynthesiswithintheteam,aswell asthechemistrydepartment.

Useofprinciplesinmedicinalchemistryinthecell-permeablecompounddesign

Thecompoundsshouldbemembrane-permeablesothattheactivityonthecellular assayswillbevisible.Thestudentwillalsouseaccuratelymeasuredandcalculated physicochemicalproperties,includingpermeabilitydatainordertoestablishan enhancedunderstandingofdifferentfactorswhichimpactspermeabilityforthese moleculeclasses,andusingthistodesigndifferentcompoundswithvariousproperties.

Outcomes

Certainoutcomesinvolvedinthisprojectserveasvalidatedandnewapproachfor potentialtargetdiscovery,servingasdesigncriteriaforthepossiblesynthesisof enhancedextensivelibraries.Thisprojectmayalsodeliverchemicalprobes,thus discoveringnewcancertargets.Therelevanceandnoveltyofthisworkforcancer therapywillallowthepublicationofdependablejournals.

References Olsen,G.,&Matthews,G.(2016).Chimeras:ProteolysisTargeting:ProteinDegradationforTherapeuticStrategy.ABCChem.Science,12(2), 234-245. Luy,G.,Tian,Q.&Palmer,G.(2017).E3UbiquitinLigaseHijackingtoEfficientlyTargettheFormationofBRD4.ChemicalWorld,22(3),123-145. Daubian,E.,&Spot,G.(2009).EnrichmentofKinase-SelectiveCompoundsEnablingQuantitativePhosphoproteomics.MolecularCellBiology, 12(2),456-478.

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