Previous high-throughput crystallographic fragment screening efforts in our laboratory yielded multiple hits against PHIP (2). These experiments were used in the assembly of the DSiPoised fragment library 14 , and the fragment hits used as the starting point for the SAMPL7 challenge and for this automated chemistry study. We selected fragment F709 (Fig. ), as it not only had unambiguous electron density at the binding site, but also revealed expansion vectors that could be diversely extended by the reaction repertoire of our roboticallyenabled array chemistry, and that would sufficiently sample the chemical landscape to provide initial SAR. Overall, these vectors enabled fragment growth to sample 3 different regions of the binding site: i) across the ZA-channel, ii) within the central hydrophobic cavity and iii) opposite the water cavity (Fig. ). F709 interacts with the protein notably via H-bonds with the backbone oxygen of proline 1340 and the side chain oxygen of serine 1392. The 5-membered furan ring is also positioned perpendicularly to tyrosine 1395 thus promoting a pi-pi interaction and the piperazine ring occupies the central hydrophobic cavity (Fig. ).