Elucidationofthemechanismofactionofnaturalproduct-basedantitumoragents.Weworkonchemicaltransformationoffusicoccins,aphytotoxin,toexploreanewseriesagentstounderstandhowitworksincells.Explorationofanewbiologicalactivityofphytotoxin.Werecentlydiscoveredanunexpectedbiologicalactivityofphytotoxinthatpromotesplantgrowth.Elucidationofthedetailsandtheagriculturalapplicationareunderwayinthelab.A“ChemicalEditing”ofphytotoxintoantitumoragents.Discoveryofnewactivityofphytotoxin.ABCCDDC1includingK-Ras,FC promotes plant growthResearch keywords・Kinase・Folding intermediate・Selectivity of drug・Drug screeningJunkoOHKANDAProfessorDr. Ohkanda’ s research interests include bioorganic chemistry, medicinal chemistry, chemical biology, and exploration of new strategies in both medicinal chemistry and plant chemical biology.Isao KIIProfessor,Ph.D.TheOhkandaResearchLabfocusesontheproblemsthatlieattheinterfaceoforganicchemistryandbiology.Weareparticularlyinterestedinthefieldofmolecularrecognitionanditsapplicationtostructure-baseddesignofpharmaceuticalagentsandchemicaltoolsthatareusefulforbetterunderstandingimportantcellularprocesses.Amajorresearchareaofthegroupincludesthedesignofmoleculesrangingfromlow-molecular-weighttomid-sizedagentscapableofrecognitionofproteininterfacestocontrolproteininteractions,aswellasintrinsicallyflexibleproteinsandregionsinbothmammalianandplantcells.Smallmoleculesindrugsandfoodsbindtoitstargetproteinsinlivingcells,andactivateorinhibititscellularfunctions,givingpharmacologicaleffects.However,smallmoleculesoftenbindtonon-targetproteinsincells,leadingtoundesiredsideeffects.Toreducesideeffectsofsmallmoleculesindrugsandfoods,weneedtoenhancethetargetselectivityofthesmallmolecules.Inourlaboratory,toenhancethetargetselectivity,wehavefocusedonatransitionalstateofthedrugtargetprotein.Itisafoldingintermediate.Ourgoalistodevelopthedrugdevelopmentplatformthatproducessmallmoleculedrugswithoutsideeffects.(Kiietal.NatureCommunications2016)forsimultaneousrecognitionofpocketandsurfaces.Byanchoringintoapocket,ourstrategyaimstodeliveraminimallysizedinhibitortoafeaturelessproteininterface.andNewmedicinalapproachesforundruggabletargets,intrinsicallydisorderedproteins,posttranslationalmodifications.polypeptideFolding intermediate(Transitional state)Depletion of the target protein in cells throughInhibition of its folding process by small molecule(Kii et al. Org Biomol Chem 2010)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). Innovative collaboration between chemistry and biologyMatureproteinOldApproachesintheOhkandaLabinclude:DesigninhibitorsofbivalentantitumorofSmall molecule kinase inhibitorTo enhance target selectivity of kinase inhibitors, we have designed small molecules that selectively bind to its folding process.Target identification of small moleculeTo identify proteins targeted by small molecule in living cells, we have developed a new system that covers cellular proteome.Development of enhanced Antibody-Drug Conjugates (ADCs)We have developed ADCs that have small molecule drugs with bio-orthogonal chemistry.Folding processDrug TargetChemical KnockdownNEWDrug TargetChemical BiologyIntegrated Bioscience Division Integrated Bioscience Division Chemical Biology LaboratoryLaboratory of Drug Target Research
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