Maneshi, Pegah; (2023) Identifying and evaluating the mode of action of novel STAT3 DNA binding domain inhibitors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Signal transducer and activator of transcription 3 (STAT3) has become a focus for cancer drug therapy since its identification as a contributor to cancer progression, angiogenesis and metastasis. Although there have been many attempts to develop a STAT3 specific inhibitor, none have been approved for use. Limitations and challenges such as, toxicity, specificity and low bioavailability are only some of the disadvantages of currently developed STAT3 inhibitors which has led to STAT3 being referred to as the undruggable target. Until recent years, the focus of these compounds was centred around the Src Homology 2 (SH2) domain and STAT3 phosphorylation, however since the identification that STAT3 is also functional in its unphosphorylated state there has been a target shift towards the DNA binding domain. Knowing the challenges in STAT3 drug discovery, this thesis set out to first develop a STAT3 specific MST assay designed to work with the published STAT3 DBD FP assay (Shih et al, 2018) in order to identify potential inhibitors and gain a greater understanding of the stoichiometry of these compounds. The data obtained through the MST assay along with crystallographic investigations were also used to further the understanding of the mode of action of the anti-helminth drug niclosamide which has been proposed as a STAT3 inhibitor but with conflicting reports on the target site of action. Although niclosamide and its analogues do show promise, IC50 values obtained for STAT3 DNA binding inhibition were higher than expected and therefore the search for a novel compound continued with the screening of over 100 ligands with 5 showing potential as DBD inhibitors. The research also adds to current questions regarding the binding site of niclosamide with STAT3:niclosamide co-crystals identifying the binding region as neither the SH2 nor the DNA binding domain. The combination of the MST assay developed and the use of crystallographic approaches in this thesis broadens our understanding of the mode of action of STAT3 inhibitors and eliminates ambiguities in their target site of action.

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