Development of Inhibitors for the Inflammasome

The NLRP3-inflammasome complex has been identified as an important regulator of inflammation, which controls the release of the pro-inflammatory cytokine interleukin-1beta. Inflammation is important in a range of therapeutic areas including Alzheimer's Disease (AD). Thus the NLRP3-inflammasome is recognized as a key target for therapeutic intervention, the subject of a recent review by the supervisory team. The supervisors have an on-going research programme regarding the development of inhibitors of the inflammasome, with two classes of lead molecules identified.
For the first class of lead molecules, a patent has been filed on a series of novel oxazaborazole compounds, the lead analogue inhibiting the release of IL-1beta with an IC50 of 0.5 muM. Whilst it has been shown that the oxazoborazoles inhibit the assembly of the multi-protein inflammasome complex, their precise mechanism is unclear. Here, chemistry-led studies towards the identification of the target will be progressed, with the synthesis of biotin-, azide- and allyl- oxazaborazole analogues to support the isolation of the target through affinity chromatography and click chemistry.
For the second class of lead molecules, a high profile paper has been published, showing that two clinically-used fenamate NSAIDs, flufenamic acid and mefenamic acid, inhibit the inflammasome through the inhibition of the Volume Regulated Anion Channel (VRAC). In addition the paper showed that mefenamic acid reversed memory loss in a mouse model of AD. The identification of VRAC as a novel target for AD is exciting and an aim of this studentship is to exploit this opportunity using two approaches. Firstly, SciFinder Scholar, a Chemical Abstracts database of all published compounds, will be thoroughly searched for commercially available analogues of the lead fenamates to form a small screening library for both the VRAC inhibition assay and the IL-1beta release assay. The Structure Activity Relationship (SAR) emerging from this screening study will be used to design and synthesise potent and selective novel VRAC inhibitors. In addition, a few commercially available VRAC inhibitors have been identified from the literature, including Tamoxifen, Phloretin, NPPB, DIDS and DCPIB. In addition, diacyl urea analogues containing either a carboxylic acid group or its tetrazole acidic bioisostere have been reported in the literature as potent VRAC inhibitors, key analogues of which will be resynthesized for evaluation in the VRAC and IL-1beta assay. Using a chemical-ligand merging strategy, components from each of the identified VRAC inhibitors will be mixed and matched, in order to synthesise a range of novel compounds for evaluation in the VRAC and IL-1beta assays. The most promising compounds will be progressed further by evaluation in the AD mouse model.
The student will join a well-equipped medicinal chemistry laboratory, with excellent access to all required analytical facilities including NMR spectroscopy and HPLC. The student will have regular (weekly) meetings with the lead chemistry-supervisor (Freeman), as well as bi-weekly multi-disciplinary meetings with the inflammation biology team (Brough & Lawrence).