Fragment-based discovery of inhibitors of the de novo purine biosynthetic enzyme PAICS


Targeting the de novo purine biosynthetic pathway is a recognised strategy in the development of anti-cancer therapeutics. PAICS (phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase) catalyses two steps of the de novo purine biosynthesis pathway; the carboxylase domain of the protein converts the substrate AIR to CAIR, followed by the ATP-dependent aspartylation of CAIR to SAICAR mediated by the synthetase domain.
Screening of a fragment library by Biacore, including compounds from the 3DFrag consortium, resulted in the identification of a selection of robust hits for human PAICS. An orthogonal functional assay screen has shown inhibition of enzyme activity by a selection of fragments, including distinct overlap with the hits identified by Biacore. Further biochemical and biophysical characterisation of these fragments has shown that they exhibit IC50’s and KD’s in the low micromolar range and are ATP-competitive. These initial hits have led to three compound series which are currently being progressed as part of a medicinal chemistry program.

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