Tankyrases constitute potential drug targets for cancer and myelin degrading diseases. We have applied a structure and biophysics driven fragment based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide -binding site, a local hot spot for fragment binding. Evolution of the fragment hit, 4-methyl-1,2-dihydroquinolin-2-one (2), along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinoline-2(1H)-one (11) reveals that the non-planar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other PARP family members. A further cycle of optimisation yielded compounds with affinities and IC50’s in the low nM range and with good solubility, PARP-selectivity and ligand efficiency.

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