E7449

E7449 is a potent inhibitor of PARP1 and PARP2 (IC_50: 1-2 nM), which, unlike many other PARP inhibitors also has significant activity against Tankyrases 1 and 2 (ca. 100 nM). It has been extensively characterized in cellular and in vivo models and is a good probe for the study of PARP1, PARP2, TNKS1 and TNKS2, but should only be used when this pharmacological profile is required. The lack of broader selectivity data should also be noted.

Users should be aware that this compound will trap PARP on DNA, a property not all PARP inhibitors possess. Compounds are reported to have good selelctivity over PARP3 and PARP6-16, with PARP4 described as having a minimal signal

The probe appears to be selective against other PARPs and the on-target pharmacology is well-characterized, but there are no data regarding broader off-target profiling - this should be better understood prior to use. The value of 'dual' inhibition would appear to be for in vivo studies, since selective PARP1/2 and tankyrase inhibitors already exist (so allowing titrations in cells). The inhibitor E7449 should be used against the target proteins PARP1, PARP2, TNKS1 and TNKS2 in a combination therapy. Several relevant examples are presented, which should encourage further exploration for either additional combination therapies.