Bechtler, Clément Martin Leopold; (2018) The design, synthesis and evaluation of Nrf2-Keap1 PPI inhibitors: a modular, virtual screening-led approach. Masters thesis (M.Phil), UCL (University College London).

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Abstract

Nrf2 (nuclear factor erythroid 2-related factor 2) is a cap’n’collar bZIP transcription factor and is the main activator of the transcription of over 100 genes that play roles in responses to oxidative stress and detoxifying xenobiotics. The main control of Nrf2 levels is exercised by Keap1 (Kelchlike ECH-associated protein 1) which facilitates the ubiquitination of Nrf2 and therefore its degradation. Keap1 is oxidation-sensitive and upon exposure to oxidants, it changes its conformation and binds Nrf2 tightly. Consequently, de novo-synthesised Nrf2 can accumulate. Following its discovery, Nrf2 received most attention in relation to cancer. Over the time, however, its implication in other pathologies have been more and more acknowledged, namely in inflammation and most importantly in neurodegenerative diseases. Especially Parkinson’s disease (PD), which is the second most common neurodegenerative disease, caused by the progressive loss of dopaminergic neurons in the substantia nigra, has been linked to oxidative stress. The role Nrf2 plays has been demonstrated in animal models of α-synuclein aggregation or chemically induced parkinsonism, where an increase in Nrf2 expression provided neuroprotection and a slowing of disease progression. Therefore, the inhibition of Keap1- mediated Nrf2 degradation presents a promising strategy for the mechanistic study and the therapy of PD. Several structures showing high potency towards Keap1 inhibition have been described, with activities in the nanomolar range. However, these compounds are large, or hydrophilic and charged. In order to develop new scaffolds, extensive virtual screening assays have been conducted which resulted in hits with promising molecular scaffolds. At the same time, chemical modifications on a known triazole structure have been performed in order to elucidate structure-activity relationships. In this thesis, the molecular modelling lead, as well the synthetic approach to both project components are described. Finally, the results of a competitive fluorescence polarisation (FP) assay for the second set of compounds are presented.

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