PDD00017273 is a potent and selective inhibitor of Poly(ADP-ribose) glycohydrolase (PARG), with an IC50 of 26 nM, and a KD of 1.45 nM. It catalyses hydrolysis of the O-glycosidic linkages of ADP-ribose polymers, reversing the effects of poly(ADP-ribose) polymerases (PARPs). PDD 00017273 suppresses the ZR-75-1 cells carring BRCA1 and BRCA2 wild type, and exhibits less potent activities against MDA-MB-436 cells carry the 5396 + 1G>A mutation in BRCA1. It is used for specific killing of cells defective in certain homologous recombination (HR) proteins such as breast cancer gene 1/2 (BRCA1/2).
PDD 00017273 is a potent inhibitor of PARG with an IC50 value of 26 nM and a Kd value of 1.45 nM[1][2].PDD 00017273 (10 μM) does not inhibit the five common cytochrome P450 enzymes. PDD 00017273 at a concentration of 30 μM moderately increases the intensity of γH2AX, and also reduces NAD/H2AX by inhibiting PARG after DNA damage. PDD 00017273 inhibits ZR-75-1 cells carrying the BRCA1 and BRCA2 wild-types, but is weakly active against MDA-MB-436 cells carrying the 5396 + 1G>A mutant BRCA1[1].At a concentration of 0.3 μM, PDD 00017273 inhibited the degradation of PAR polymers in MCF7 cells, and also reduced the viability of BRCA1, BRCA2, PALB2, FAM175A, and BARD1 depleted cells. PDD 00017273 blocks replication forks and induces DNA damage that requires homologous recombination (HR) to repair[2].
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