Design and synthesis of novel small molecule inhibitors of MYST proteins

Epigenetics is defined as alterations to gene expression, resulting from indirect changes to DNA which occur during post-translational modification events. These changes in the phenotypical expression of a cell occur without alterations being made to the underlying genotype. One of the major epigenetic events which occur in cells is histone acetylation, with this process ultimately being governed by Histone acetyltransferase (HAT) proteins. This thesis focusses on the development of novel small molecule inhibitors of the MOZ (or MYST3) protein, a HAT protein which belongs to the MYST family of proteins. The MOZ protein has been identified to be an upstream regulator of a range of cellular pathways which govern cellular senescence and cancer formation. Furthermore this protein has also been identified to play a role in embryonic development. The project began with a HTS leading of over 243,000 compounds, leading to the identification of one compound which was deemed to be an acceptable starting point for a medicinal chemistry campaign. This initial hit was developed into a small class of analogues to begin the SAR exploration of the MOZ binding pocket. Chapter 2 discusses the development of the 2nd generation analogues. This research involved the exploration of three different streams of compounds, all of which were identified to have slightly different binding modes within the MOZ protein. The compounds explored in this chapter focused on probing the SAR surrounding the “right hand side” of the common core. In chapter 3 the SAR surrounding the “left hand side” of the common core was explored. This work included exploration and development of a range of synthetic procedures to allow for the development of a broader range of small molecule inhibitors of the MOZ protein. Chapter 4 discusses the further development of one class of compounds identified in the 2nd generation exploration, this work resulted in the development of the 3rd generation inhibitors of the MOZ protein. This class of compounds resulting in an increase in the potency of inhibitors, whilst furthering the exploration of the SAR at the “right hand side” of the common core. In chapter 5 development of replacements for the common core were investigated. Until this point of the project all small molecule inhibitors of the MOZ protein had be reliant on a specific core structure to which variations to the surrounding regions had be included. This work led to the development of a class of MOZ inhibitors which were able to rival the potency of the 2nd and 3rd generation analogues but had the added bonus of opening up a wide scope of core changes for future exploration. Overall this project resulted in the identification of a large number of highly potent classes of small molecule inhibitors of the MOZ protein. Furthermore a favourable replacement for the common core of these molecules was identified and the initial SAR for this new class of compounds was undertaken, paving the way for future exploration of inhibitors of the MOZ protein.