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Novel 3-D Building Blocks for Elaboration of Fragments to Lead-like Compounds

As recently highlighted by researchers at Astex, one of the key synthetic challenges in fragment-based drug discovery is the elaboration of a fragment hit into a more active, lead-like compound. At present, this is a slow, time-consuming stage of the hit identification process, especially when elaboration in 3-dimensions is desired. As a result, the O’Brien group is currently exploring the development of a modular synthetic platform for the elaboration of (typically 2-D) fragment hits (identified by X-ray crystallographic screening) into 3-D lead-like compounds for biological assays. Our focus is on the development of a small library (ca 25 compounds) of novel 3-D bifunctional building blocks, each with its own distinct vector in 3-D space for growth. Methodology, ideally automated, for the attachment of fragments to the building blocks together with functionalisation of the structure-activity relationship (SAR) handle will be explored. This project has received support from a Royal Society Industry Fellowship with AstraZeneca (2019-2022). In addition, the novel 3-D building blocks have been developed with EPSRC IAA and HEIF funding, and are currently being commercialised through a collaboration with Redbrick Molecular.