This poster reports the discovery of compounds 3 and 4 as advanced fragment leads for Kynurenine Aminotransferase isoform II (KATII), a protein that is associated with the negative symptoms of schizophrenia. Starting with the initial fragment hit 1 (hKAT II IC50 &gt;1440 uM), we improved the biophysical and biochemical activity of this series via introduction of a sulfonamide group. The methyl sulfonamide 2 afforded a hKATII IC50 = 420 uM, and the phenyl sulfonamide 3 afforded a hKATII IC50 = 80 uM, and both compounds were active in all three biophysical assays (NMR, SPR and TSA). A series of optimization steps and follow-up libraries were employed to discover 4, which showed significant improvement across all assays with hKAT II activity of 3.6 μM, and a ligand efficiency of 0.27. X-ray crystallography confirmed that compound 4 bound to the active site of KATII with the unexpected participation of a second molecule of the inhibitor.

Discovery of KATII inhibitors via a fragment-based approach

251st National Meeting (2016)

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