Elucidationofthemechanismofactionofnaturalproduct-basedantitumoragents.Weworkonchemicaltransformationoffusicoccins,aphytotoxin,toexploreanewseriesagentstounderstandhowitworksincells.Explorationofanewbiologicalactivityofphytotoxin.Werecentlydiscoveredanunexpectedbiologicalactivityofphytotoxinthatpromotesplantgrowth.Elucidationofthedetailsandtheagriculturalapplicationareunderwayinthelab.A“ChemicalEditing”ofphytotoxintoantitumoragents.Discoveryofnewactivityofphytotoxin.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.polypeptideFolding intermediate(Transitional state)(Kiiet al. Org BiomolChem2010)Innovative collaboration between chemistry and biologyMatureproteinOldJunkoOHKANDAProfessorDr. Ohkanda’ s research interests include bioorganic chemistry, medicinal chemistry, chemical biology, and exploration of new strategies in both medicinal chemistry and plant chemical biology.Smallorganiccompoundsinmedicinalsubstancesbindtospecificproteintargetsinlivingcells,therebymodulatingtheirbiologicalactivity,andresultinginpharmacologicaloutcomes.However,suchcompoundsmayalsonon-specificallybindtonon-targetproteinsinthecellularmilieu,thusleadingtoundesiredadverseeffects.Tocircumventsuchoff-targeteffectsofsmallmolecules,itisimperativetoimprovetheirselectivitytowardsthetarget.Ourlaboratoryhasundertakeninvestigationsintothetransitionalstateofthetargetprotein,whichcorrespondstoanintermediatestateofproteinfolding.Ourultimateobjectiveistodeviseadrugdevelopmentplatformthatcanyieldsmallmoleculetherapeuticswithminimalsideeffects.(Kiietal.NatureCommunications2016)Isao KIIProfessor,Ph.D.Research keywords・Kinase・Folding intermediate・Selectivity of drug・Drug screeningTheOhkandaResearchLabfocusesontheproblemsthatlieattheinterfaceoforganicchemistryandbiology.Weareparticularlyinterestedinthefieldofmolecularrecognitionanditsapplicationtostructure-baseddesignofpharmaceuticalagentsandchemicaltoolsthatareusefulforbetterunderstandingimportantcellularprocesses.Amajorresearchareaofthegroupincludesthedesignofmoleculesrangingfromlow-molecular-weighttomid-sizedagentscapableofrecognitionofproteininterfacestocontrolproteininteractions,aswellasintrinsicallyflexibleproteinsandregionsinbothmammalianandplantcells.forsimultaneousrecognitionofpocketandsurfaces.Byanchoringintoapocket,ourstrategyaimstodeliveraminimallysizedinhibitortoafeaturelessproteininterface.andthrough inhibition of the folding process by small molecules.Newmedicinalapproachesforundruggabletargets,intrinsicallydisorderedproteins,posttranslationalmodifications.Antitumor agentsNaturally-occurring phytotoxin fusicoccin (FC)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). ApproachesintheOhkandaLabinclude:DesigninhibitorsofbivalentantitumorofABCCDDCA1includingK-Ras,FC promotes plant growthFolding processChemical KnockdownDepletion of the target protein in cellsChemical BiologyDrug TargetNEWDrug TargetIntegrated Bioscience Division Integrated Bioscience Division Chemical Biology LaboratoryLaboratory of Drug Target Research
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