Shih, Po-Chang; (2019) The design, synthesis and evaluation of small-molecule inhibitors of signal transducer and activator of transcription 3 (STAT3). Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Anti-cancer drug discovery targeting the signal transducer and activator of transcription 3 (STAT3), has been active for more than a decade following a finding that aberrant activity of this transcription factor is involved in more than 70% of cancers. There are two main approaches to directly abating STAT3 activity, one is to inhibit STAT3 homo-dimersation by targeting the SH2 or transcriptional activation domains, and the other is to prevent STAT3 from interacting with DNA targeting its DNA-binding domain (DBD). The aims of this project are to discover novel STAT3 DBD inhibitors for further development and to develop a biophysical assay for the evaluation of STAT3 DBD inhibitors. The foundation to this project involved an observation that a small molecule fragment derived from the STAT3 dimerisation inhibitor BP-1 -102 occupied a site adjacent to the DBD when co-crystallised with a STAT3 (127-688) construct. Consequently, a series of small-molecule fragments were designed based upon the BP-1 -102 fragment. The compounds were synthesised, characterised and biologically evaluated in an attempt to understand the structure-activity relationships (SARs) associated with BP-1 -102. It was anticipated that by modifying the BP-1 -102 structure, the mode of action would be shifted from inhibition of STAT3 dimerisation to blocking STAT3 DNA-binding. However, the small-molecule fragments that were synthesised did not show significantly improved binding affinity compared to the BP-1 -102 fragment. Details of a STAT3 DBD inhibitor, inS3-54, were disclosed in 2014 and 2016, so the focus of the project shifted towards modifying this new inhibitor scaffold. A series of novel STAT3 DBD inhibitors were designed and docked in silico, then synthesised and biologically tested in vitro. Due to the lack of cell-free assays for evaluating STAT3 DBD inhibitors, a new orthogonal fluorescence polarisation (FP) assay was developed and validated to assess ligand binding. The preliminary results suggest some of the new structures are able to inhibit STAT3 DNA-binding in this FP assay after 24 hr incubation. Such compounds are potential lead structures for further development as STAT3 inhibitors.

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