The synthesis and evaluation of WWP2 E3 ubiquitin ligase inhibitors as anti-cancer leads

Rigby, Jake Matthew (2024) The synthesis and evaluation of WWP2 E3 ubiquitin ligase inhibitors as anti-cancer leads. Doctoral thesis, University of East Anglia.

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Abstract

The ubiquitin-proteasome system (UPS) is the major system involved in the regulation of cellular protein quality and quantity. The UPS does this in a highly selective manner by tagging redundant cellular proteins with ubiquitin, which leads to their degradation by the 26S proteasome. Within the ubiquitin-proteasome system, the WW-domain containing HECT E3 ubiquitin ligase 2 (WWP2) is responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins. WWP2s dysregulation is present in several diseases, most notably in cancer. WWP2 therefore represents a therapeutic target for small-molecule inhibition for cancer therapy.

This doctoral thesis focusses on the generation of small molecule inhibitors of WWP2 as anticancer leads, with initial starting compounds identified from high-throughput screenings. This thesis describes the synthetic work undertaken to produce WWP2 inhibitors via a rational drug design approach. The production of focussed libraries surrounding the identified hits was aided by molecular docking studies and, in two cases, co-crystal structures. In the course of this work, the reproduction of 9 hit molecules or molecules of interest for crystal soaking studies and analogue synthesis of 4 different lead compounds was pursued. Approximately 100 derivative compounds have been investigated as part of this aim.

The results of this investigation show little improvement in inhibitory data against WWP2 in any of the hit compounds pursued into analogues synthesis, which points towards some issues surrounding strategy with respect to hit validation. Issues surrounding hit IC50 value reproducibility identified impure NCI samples. The identification of PAINs and nuisance compounds as hits investigated also hampered the production of inhibitors of WWP2. The issues identified in the processes prior to hit-to-lead optimisation in the course of this work should be addressed to overcome the investigation of unproductive leads. A more solid experimental foundation with which to choose analogues for synthesis is also desirable. Additionally, several analogue series are currently being investigated as promising WWP1 inhibitors, a close relative of WWP2 also present as a therapeutic target against cancer.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Chemistry
Depositing User:	Nicola Veasy
Date Deposited:	11 Jul 2024 08:52
Last Modified:	11 Jul 2024 13:21
URI:	https://ueaeprints.uea.ac.uk/id/eprint/95861
DOI:

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