| Summary: | Fragment based drug discovery has become an important method in biomedical research. In particular, it has enabled academic researchers to develop drug-like compounds and chemical probes which can be used for target validation. Recent developments at Diamond Light Source have made X-ray crystallography a viable primary fragment screen. The hits identified by X-ray screening are in general too weak to be verified by orthogonal solution assays, yet such information is a common requirement in medicinal chemistry operations. Progressing weak hits to a potent lead series requires changes not only to the periphery, where conventional SAR operates, but also to the core of the compound. To overcome the problem, I introduce the concept of poised fragment screening. Poised fragments can be synthesised in one step from commercially available starting materials using robust, high yielding reactions. As a result, a library of analogues can be synthesised quickly and at relatively low cost. In this thesis I report the design and purchase of a 776-compound, chemically diverse poised fragment library (DSPL) for screening using X-ray crystallography, which is in regular use at Diamond. To aid researchers performing follow-up campaigns of poised hits, I developed a computational tool, XPoise, which systematically builds virtual libraries of follow-up compounds using poised reactions. Follow-up campaigns against four epigenetic proteins revealed the benefit of using poised chemistry over traditional methods such as SAR by catalogue. Weak hits were improved into lead compounds with modest potency alongside structural data. Finally, a lead series of PHIP(2) inhibitors was elaborated using bespoke organic synthesis and late stage biotransformation to build complex, chiral compounds in the search for a potent and selective chemical probe.
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