Fig. 3
From: Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death
The 6´-thiocarbonyl group contributes strongly to the potency. a, b Crystal structures of human PARG bound to JA2131 a and JA2120 b. JA2131 and JA2120 occupy the adenine-binding pocket of hPARG in the same orientation as JA2-4. The 6´-thiocarbonyl of JA2131 makes a direct van der Waals contact with the main chain amide of Asn869 (3.6 Å) a, whereas the 6´-carbonyl of the less potent inhibitor JA2120 makes water-mediated hydrogen bonds to the main chain amide of Asn869 (4.3 Å) and the main chain carbonyl of Phe902 b. These findings indicate that the 6´-thiocarbonyl group of JA2-4 series inhibitors increases potency by introducing a direct interaction with hPARG. c The structure-activity relationships (SAR) for JA2-4 series inhibitors. The direct interaction between the 6´-thiocarbonyl group of JA2131 and hPARG increases potency more than 50-fold in comparison to JA2120. PDB code: 6OA1 (PARG/JA2120), 6OA3 (PARG/JA2131). Source Data are provided as a Source Data file.
