The Development of Vinylheteroarene Linkers for Proteinogenic Cysteine Modification and Studies Towards Applying (+)-Discodermolide as a Novel Payload in Antibody-Drug Conjugates
type: CreativeWork
description: The 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 lin…
abstract: The 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 lin…
author: Seki, Hikaru
language: eng
keywords: protein modification, antibody-drug conjugates, biotherapeutics
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2021-12-05
date modified: 2026-07-22T22:24:16Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.85734