Research into the chemical biology of bromodomains has been driven by the development of acetyl-lysine mimetics. The ligands are typically anchored by binding to a highly conserved asparagine residue. PHIP(2) is an atypical bromodomain containing a threonine residue in place of the conserved asparagine. The parent protein, PHIP, has been linked to disease progression in diabetes and cancers but thus far has proven an elusive target. We have discovered the first reported hits of PHIP(2) by combining the sensitivity of X-ray crystallography, used as a primary fragment screen, with a strategy for rapid follow-up synthesis using a chemically-poised fragment library. The library was designed to allow straightforward modification of screening hits both peripherally and in the core using parallel chemistry. The development of an AlphaScreen competition assay allowed measurement of compound IC<sub>50</sub> against PHIP(2). The follow-up libraries of four poised fragment hits improved potency into the sub-mM range, alongside good ligand efficiency and detailed structural data.

Design and utilisation of a poised fragment library in the search for inhibitors of PHIP(2), an atypical bromodomain

251st National Meeting (2016)

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