Revisiting the PARP inhibitors

This month, we updated our PARP inhibitor records based on a new and important publication reporting potency and selectivity information for 11 PARP family inhibitors that are commonly used as chemical probes (Thorsell et al., 2016). This paper reports several key new observations about the activity of these inhibitors, prompting us to revisit and update the probe and historic compound records.

Importantly, this work quantified direct inhibition of PARP enzyme activity – ADP ribosylation – rather than binding or another indirect readout. The authors also assessed the activity observed in the presence of isolated protein catalytic domains compared with the full-length proteins, and for PARP1, PARP2 and PARP3, they found that the isolated catalytic domains were notably less active than their full-length counterparts, indicating that the use of isolated catalytic domains in prior studies may have masked potency differences among these inhibitors.

Accordingly, we updated our PARP inhibitor probe records to include these new and important data. The major implications are:

  • For the selective inhibition of PARP1 and PARP2, veliparib and niraparib are likely the best probes available.
  • Likewise, for the selective inhibition of TNKS1 and TNKS2, AZ-6102 and IWR-1 (coming soon) are likely the best options.
  • For broad specificity PARP inhibition, olaparib, rucaparib, and talazoparib are good options.

 

We are also pleased to announce the following new probes have been published on the Portal so far this month:

CCT251545 CDK8, CDK19

CCT251236 PIR

A-196 KMT5B, KMT5C 

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