Thesis

The design, synthesis and optimisation of small molecule ERAP1 inhibitors

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2023
Thesis identifier
  • T17251
Person Identifier (Local)
  • 201885374
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is an intracellular aminopeptidase based in the endoplasmic reticulum. Peptides are cleaved by ERAP1 then subsequently presented on the cell surface for signalling with the immune system. Inhibition of ERAP1 modulates the adaptive immune response and therefore has indications as a target for cancer or autoimmune diseases. Described herein is the design and syntheses of three distinct chemical series, within the hit to lead drug discovery stage, which inhibit ERAP1: the Benzazepine series, Cyclohexyl Acid series and Proline series [see Table 1 in thesis]. These series were optimised in terms of potency, physicochemical properties and ligand efficiencies. Structure-based drug design, based on ERAP1 X-ray crystallography, was used as the primary tool to optimise potency by achieving new protein-ligand interactions with ERAP1. Physicochemical property optimisation was guided by literature best practices to reduce the probability of developability risks such as poor solubility and high metabolic clearance. For the Benzazepine Series, although progress was achieved in terms of ERAP1 potency and physicochemical property optimisation, a data-driven decision was made to pause the chemistry on the series due to the shortcomings of murine Endoplasmic Reticulum Aminopeptidase Associated with Antigen Processing (ERAAP1) activity. Progress was also made in the Proline series in terms of biochemical potency, but the series generally showed poor cellular activity. For the Cyclohexyl Acid series, highly ligand efficient examples in a desirable physicochemical property space were developed, with several examples exhibiting subnanomolar cellular potency. Several Cyclohexyl Acid compounds were tested against closely related enzymes Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) and Insulin-Regulated Aminopeptidase (IRAP), and were found to be highly selective for ERAP1 over these other enzymes. As a result of satisfying all project objectives, the Cyclohexyl Acid series transitioned into Lead Optimisation for further development.
Advisor / supervisor
  • Reid, Marc
  • Palmer, David
  • Lindsay, David
  • Tomkinson, Nick
Resource Type
Note
  • Previously held under moratorium in the Chemistry Department (GSK) from 1st February 2023 until 4th March 2025. The confidentiality statement in this thesis does not apply.
DOI
Date Created
  • 2022
Funder
Embargo Note
  • The digital version of this thesis is restricted to Strathclyde users only until 1st February 2028.

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