Laboratory of Drug Target ResearchIsao KIIProfessor,Ph.D.Research keywords・Kinase・Folding intermediate・Selectivity of drug・Drug screeningSmallmoleculesindrugsandfoodsbindtoitstargetproteinsinlivingcells,andactivateorinhibititscellularfunctions,givingpharmacologicaleffects.However,smallmoleculesoftenbindtonon-targetproteinsincells,leadingtoundesiredsideeffects.Toreducesideeffectsofsmallmoleculesindrugsandfoods,weneedtoenhancethetargetselectivityofthesmallmolecules.Inourlaboratory,toenhancethetargetselectivity,wehavefocusedonatransitionalstateofthedrugtargetprotein.Itisafoldingintermediate.Ourgoalistodevelopthedrugdevelopmentplatformthatproducessmallmoleculedrugswithoutsideeffects.(Kiietal.NatureCommunications2016)Integrated Bioscience Division Small 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 processpolypeptideMatureproteinFolding intermediate(Transitional state)NEWDrug TargetOldDrug TargetChemical KnockdownDepletion of the target protein in cells throughInhibition of its folding process by small moleculeChemical BiologyInnovative collaboration between chemistry and biology(Kii et al. Org Biomol Chem 2010)Chemical Biology LaboratoryJunkoOHKANDAProfessor,Ph.D.Dr. Ohkanda’ s research interests include bioorganic chemistry, medicinal chemistry, supramolecular chemistry, chemical biology, and new strategies in medicinal chemistry.ApproachesintheOhkandaLabinclude:Intracellulargenerationofagentsthatdisruptproteininteractions.Westudyanewapproachofintroducinglargemoleculesbyexploitingtemplatesynthesisonthetargetedproteinsurfaces.Designofbivalentinhibitorsforsimultaneousrecognitionofpocketandsurfaces.Byanchoringintoapocket,ourstrategyaimstodeliveraminimallysizedinhibitortoafeaturelessproteininterface.Elucidationofthemechanismofactionofnaturalproduct-basedantitumoragents.Weworkonchemicaltransformationoffusicoccins,aphytotoxin,toexploreanewseriesofantitumoragentsandtounderstandhowitworksincells.CDMultivalentmoleculesgeneratedbyassemblingofsmallmodulesarecapableofmodulationofintracellularproteininteractions.Integrated Bioscience DivisionABCDACTheOhkandaResearchLabfocusesontheproblemsthatlieattheinterfaceoforganicchemistryandbiology.Weareparticularlyinterestedinthefieldofmolecularrecognitionanditsapplicationtostructure-baseddesignofpharmaceuticalagentsandchemicaltoolsthatareusefulforabetterunderstandingofimportantcellularprocesses.Amajorrecentareaofresearchofthegroupincludesthedesignofmoleculesrangingfromlow-molecular-weightenzymeinhibitorstomid-sizedagentscapableofrecognitionofproteininterfacestocontrolproteininteractions.Peptides,naturalproducts,heterocycles,andmetalcomplexesareofinterestasthebuildingblocksforrationaldesigningofartificialbiomolecules.1
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