University of Cambridge
Development of stapled peptide targeted covalent inhibitors and synthesis of novel ADC payloads for applications in cancer therapy
Abstract
dc:description.abstractCancer is one of the leading causes of deaths worldwide with 1 in 2 people estimated to develop the disease during their lifetimes. While great progress has been made in curing cancers, new therapeutics are still necessary to tackle this collection of diseases and minimise side-effects. This thesis presents two approaches towards the development of novel bioactive molecules with application in cancer therapeutics. 1) Development of stapled peptide–targeted covalent inhibitors (SPTCIs) of p53–MDM2 protein–protein interaction (PPI). Herein, the development and synthesis of three novel electrophilic staples and four stapled peptides are described. The stapled peptides bear moieties to covalently target a surface-exposed lysine residue on MDM2, an important anti-apoptotic protein overexpressed in many cancer cells. Led by computational modelling and kinetic studies on stability and reactivity of the electrophiles, an SPTCI with an apparent Kd of 7.1 nM was discovered. The stapled peptide was built using two-component Cu-catalysed azide-alkyne cycloaddition (CuAAC) and an activated ester electrophile for targeted covalent inhibition. The peptide showed selective and complete covalent binding to MDM2. Crucially, this proof-of-concept study sets the basis for the development of SPTCIs for a wider range of PPIs. 2) Novel total synthesis of hemiasterlin and its use as a payload in antibody–drug conjugates (ADCs). This thesis details the novel synthesis of hemiasterlin, an anti-mitotic marine natural product with low- to sub-nM potencies against several cancer cell lines. Rapid construction of hemiasterlin was achieved, through a four-component Ugi reaction, in total 14 steps (longest linear sequence of 10 steps) in 11% overall yield. The convergent synthetic route also enabled the synthesis of taltobulin (HTI-286), a similarly potent synthetic analogue. Through the synthesis of complex linker-drug molecules, two ADCs were made to investigate the potential of the two molecules as payloads. Remarkably, the conjugates were found to have mid-pM cytotoxicity against antigen-expressing breast cancer cell lines and no appreciable activity against antigen-negative cancer cells.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2020
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Charoenpattarapreeda, Jiraborrirak
- Advisor dc:contributor.advisor
-
- Spring, David R
Subjects
dc:subject × 12Rights
dc:rightsIdentifiers
dc:identifier.*- Author Identifier
- 0000-0002-0316-9608
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/317007