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dc.contributor.authorSeki, Hikaru
dc.date.accessioned2022-06-23T11:27:32Z
dc.date.available2022-06-23T11:27:32Z
dc.date.submitted2021-12-05
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338324
dc.description.abstractThe Development of Vinylheteroarene Linkers for Proteinogenic Cysteine Modification and Studies Towards Applying (+)-Discodermolide as a Novel Payload in Antibody-Drug Conjugates Hikaru Seki Antibody-drug conjugates (ADCs) are an emerging class of anticancer agents which combine the cell-targeting properties of a monoclonal antibody and the cytotoxicity of a small molecule drug. The antibody, cytotoxin and the covalent linker which connects the two units must be optimised for the ADC to have favourable pharmacokinetic, toxicology, and overall pharmacological profiles. The first project describes the design, synthesis, and evaluation of vinylheteroarene linkers for the post-translational modification of proteinogenic cysteine residues. It was hypothesised that the variable heteroarene ring electronics would greatly affect the conjugate addition reaction rate and resulting bioconjugate stability. Thus, a panel of vinylheteroarenes with differing heterocyclic groups were synthesised and evaluated for their suitability. Using small molecule model systems, vinylheteroarene linkers were assessed for cysteine reactivity and chemoselectivity, and conjugate stability to identify the optimum linker. The lead linker was utilised to modify a number of protein substrates with various functionality, including the synthesis of a homogeneous, stable and biologically active ADC. The reagent was also efficient in labelling proteome-wide cysteines in cell lysates. The efficiency and selectivity of these reagents as well as the stability of the products makes them suitable for the generation of biotherapeutics or studies in chemical biology. The second project describes studies towards using (+)-discodermolide as a cytotoxic payload in ADCs. Discodermolide is a polyketide natural product which displays potent activity as an antimitotic agent and is known to be effective against a range of malignancy types. It was desired was to attach discodermolide to an antibody using a cleavable linker which would enable traceless release of the cytotoxin. The alcohol groups in discodermolide presented an opportunity to achieve this in a chemically tractable way. Thus, a valine-alanine-para-aminobenzylcarbonyl-hemiaminal linker was designed for the selective cleavage and payload release by lysosomal cathepsin enzymes. Importantly, this linker strategy allows the synthesis of linker-payloads in one synthetic step, making this a promising approach for the rapid assembly of ADCs using unexplored alcohol cytotoxins. Using this linker, a discodermolide ADC was successfully synthesised which can be used for biological evaluation.
dc.description.sponsorshipGeoffrey Moorhouse Gibson Studentship in Chemistry Trinity College
dc.rightsAll Rights Reserved
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/
dc.subjectprotein modification
dc.subjectantibody-drug conjugates
dc.subjectbiotherapeutics
dc.titleThe Development of Vinylheteroarene Linkers for Proteinogenic Cysteine Modification and Studies Towards Applying (+)-Discodermolide as a Novel Payload in Antibody-Drug Conjugates
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.date.updated2022-06-22T20:01:48Z
dc.identifier.doi10.17863/CAM.85734
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved/
rioxxterms.typeThesis
cam.supervisorSpring, David R
cam.depositDate2022-06-22
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2023-06-23


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