Thesis
Exploiting DNA-encoded library : technology for the discovery of novel antibody recruiting molecules against LOX-1
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2022
- Thesis identifier
- T17011
- Person Identifier (Local)
- 201853925
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Bifunctional small molecules, such as Proteasome Targeting Chimeras (PROTACs), and Antibody Recruiting Molecules (ARMs), are used increasingly in medicinal chemistry due to their ability to induce protein-protein interactions to target traditionally “undruggable” proteins. Known ligands can be excellent starting points for their design, but many targets lack known binders. Moreover, most drug discovery techniques were developed for identification of monovalent small molecule drugs, and may not be suited to bifunctional drug discovery. Selection and creative use of drug discovery platforms can therefore be critical to success. The approach taken in this work is shown in Figure 0.1. Novel ARMs against Lectin-type Oxidized LDL Receptor 1 (LOX-1) are identified based on a DNA-encoded library selection. This technology facilitates simultaneous screening of billions of compounds, and identifies even functionally inactive binders. This feature nicely complements the ARM modality: nonfunctional binders may still make functional ARMs. Conveniently, each library member is attached to a DNA “barcode” for identification, meaning a suitable linker trajectory is evident for every hit. Structure activity relationship (SAR)-driven analysis of the encoded library screening data identified 17 compounds for initial off-DNA synthesis. The compounds were synthesised with a functional handle at the position used for DNA conjugation, facilitating single-step ARM synthesis from the parent ligand. Binders were confirmed by ASMS and thermal shift, and a “small molecule ELISA” assay was developed to simulate antibody recruitment at the cell surface. Six of the 17 ARMs demonstrated ternary complex formation which could be competed with the parent LOX-1 ligand, with nanomolar EC50 values. SAR of the lead series was further demonstrated by an array synthesis of 28 compounds, which were analysed in a high throughput competition ELISA. The active ARMs will be progressed to cellular assays, the ultimate goal being selective killing of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which play an immune suppressive role in many cancers and correlate to poor response to immune checkpoint inhibition. These cells have also been recently associated with fatal outcomes in COVID-19 patients, meaning these ARMs could have multiple therapeutic applications.
- Advisor / supervisor
- Sender, Matt
- Clohessy, Tom
- Jamieson, Craig
- Resource Type
- Note
- Previously held under moratorium in the Chemistry department (GSK) from 12th June 2022 until 12th June 2024.
- DOI
- Funder
- Embargo Note
关系
项目
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File | 2024-06-20 | 非公开 |