Olaparib

Olaparib provides an effective tool compound for investigating the role of the PARPs in DNA repair and other biological contexts. However, olaparib inhibits predominantly PARPs 1 and 2, leaving the other 15 family members, to potentially compensate to some extent for this inhibition. There is some evidence that olaparib works primarily through trapping of PARP on damaged DNA, sequestering the enzyme, rather than through direct inhibition of catalytic function. Given this, for certain experiments it is advisable to use veliparib, either as a replacement or for parallel studies, which appears not to trap PARP but to inhibit it's catalytic function.

Olaparib is a PARP 1/2/3 inhibitor. This agent is an excellent tool to study PARP inhibition in both the cellular and in vivo setting. However, an important study about the mechanism of these probes appeared in 2012 (Murai et al., Cancer Res. 2012, 72, 5588-5599). In this study, the authors examined the ability of niraparib, olaparib and veliparib to trap PARP1/2 enzymes at the site of DNA damage as opposed to examining merely their activity as inhibitors of the catalytic function of the enzyme. The authors found that the cellular toxicity tracked with the trapping potential (which was different for each drug) rather than each drugs catalytic efficiency (which was similar for each drug). The ranking of each drug for trapping efficiency was found to be niraparib > olaparib >> veliparib. Investigators should thoroughly evaluate their needs when choosing the appropriate PARP inhibitor based upon this altered mechanistic insight.

Portal staff comment: A new publication appeared in December 2016 (PMID 28001384) indicating that veliparib and niraparib are more selective than olaparib among PARP family proteins.

Olaparib has actvity against PARPs 1, 2, 3 and 4; it has little activity against other members of the PARP family.