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.
| Date of Award | 9 Feb 2023 |
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| Original language | English |
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| Awarding Institution | - University Of Strathclyde
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| Sponsors | University of Strathclyde |
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| Supervisor | David Lindsay (Supervisor) & John Murphy (Supervisor) |
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