An iterative screen was subsequently carried out with the intention of expanding the pool of hit compounds and identifying BCL6 hits with higher covalent modification yields. For this, a new 352-membered library of SFbased reactive fragments was designed based on a similarity search of available amine-functionalised fragments using the top four original hits (2f-i). The library was generated by HTC, incubated with BCL6 in a D2B fashion, and subsequently analysed by intact protein LC-MS. The extent of covalent modifications observed for this screen were markedly higher, with many further hits discovered (2m-t). This included five reactive fragments which gave covalent modification yields greater than the maximum modification yields observed in the original screen, and three hits with over 50% modification (Fig. &). The meta-substituted benzamides gave the higher modification yields, and several different groups in the meta-position were well-tolerated. Other hits showed that different N-containing saturated heterocycles with alternative heteroatom links to aryl groups were also tolerated by the binding pocket.