?Design?Elucidationofthemechanismofactionofnaturalproduct-basedantitumoragents.Weworkonchemicaltransformationoffusicoccins,aphytotoxin,toexploreanewseriesagentstounderstandhowitworksincells.?Explorationofanewbiologicalactivityofphytotoxin.Werecentlydiscoveredanunexpectedbiologicalactivityofphytotoxinthatpromotesplantgrowth.Elucidationofthedetailsandtheagriculturalapplicationareunderwayinthelab.ABCCDDACA1includingK-Ras,FC promotes plant growthIntegrated Bioscience Division Integrated Bioscience Division Chemical Biology LaboratoryLaboratory of Drug Target ResearchJunkoOHKANDAProfessorIsao KIIProfessor,Ph.D.Research keywords?Kinase?Folding intermediate?Selectivity of drug?Drug screeningofbivalentantitumorofinhibitorsforsimultaneousrecognitionofpocketandsurfaces.Byanchoringintoapocket,ourstrategyaimstodeliveraminimallysizedinhibitortoafeaturelessproteininterface.andDr. Ohkanda’ s research interests include bioorganic chemistry, medicinal chemistry, chemical biology, and exploration of new strategies in both medicinal chemistry and plant chemical biology.TheOhkandaResearchLabfocusesontheproblemsthatlieattheinterfaceoforganicchemistryandbiology.Weareparticularlyinterestedinthefieldofmolecularrecognitionanditsapplicationtostructure-baseddesignofpharmaceuticalagentsandchemicaltoolsthatareusefulforbetterunderstandingimportantcellularprocesses.Amajorresearchareaofthegroupincludesthedesignofmoleculesrangingfromlow-molecular-weighttomid-sizedagentscapableofrecognitionofproteininterfacestocontrolproteininteractions,aswellasintrinsicallyflexibleproteinsandregionsinbothmammalianandplantcells.ApproachesintheOhkandaLabinclude:Newmedicinalapproachesforundruggabletargets,intrinsicallydisorderedproteins,posttranslationalmodifications.Antitumor agentsNaturally-occurring phytotoxin fusicoccin (FC)“ChemicalEditing”ofphytotoxintoantitumoragents.Discoveryofnewactivityofphytotoxin.Bioorg. Med. Chem. Lett. 2021, Chem. Commun.2020(Cover), Chem. Asian J. 2020,Chem. Eur. J. 2019(Hot Paper), Chem. Eur. J. 2018(VIP Paper). Smallorganiccompoundsinmedicinalsubstancesbindtospecificproteintargetsinlivingcells,therebymodulatingtheirbiologicalactivity,andresultinginpharmacologicaloutcomes.However,suchcompoundsmayalsonon-specificallybindtonon-targetproteinsinthecellularmilieu,thusleadingtoundesiredadverseeffects.Tocircumventsuchoff-targeteffectsofsmallmolecules,itisimperativetoimprovetheirselectivitytowardsthetarget.Ourlaboratoryhasundertakeninvestigationsintothetransitionalstateofthetargetprotein,whichcorrespondstoanintermediatestateofproteinfolding.Ourultimateobjectiveistodeviseadrugdevelopmentplatformthatcanyieldsmallmoleculetherapeuticswithminimalsideeffects.(Kiietal.NatureCommunications2016)Small molecule kinase inhibitorTo enhance the target selectivity of the kinase inhibitors, we designed small molecules that selectively bind to their folding process.Target identification of small moleculeTo identify the proteins targeted by small molecules in living cells, we developed a new system that covers the cellular proteome.Development of enhanced Antibody-Drug Conjugates (ADCs)We have developed ADCs that contain small-molecule drugs with bio-orthogonal chemistry.through inhibition of the folding process by small molecules.polypeptideFolding intermediate(Transitional state)Folding processChemical KnockdownDepletion of the target protein in cells(Kiiet al. Org BiomolChem2010)Drug TargetChemical BiologyNEWOldDrug TargetInnovative collaboration between chemistry and biologyMatureprotein
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