Beware of confounding effects: the case of PARP

A new article in which the groups of Jordi Mestres and José Yelamos, both at the IMIM, have collaborated, represents an example of how many gaps there are in our knowledge of biological processes, and of the potential danger of this lack of knowledge might cause.

In this case, the focus is small molecules. These are widely used in chemical biology, usually as inhibitors to try to understand the function of specific proteins they target. But despite the fact they are commonly used, we don’t have a complete knowledge of their target profile, and they might have unknown off-target interactions. Therefore the conclusions we get from their effects might include a big confounding effect that is not taken into account.

In this paper published in ACS Chemical Biology Mestres and Yelamos show that this is precisely the case with the PJ34 small molecule, which is used to study the role of the PARP proteins, a family of proteins which play an important role in DNA repair, cell death and proliferation, and in the stabilization of the genome.

Some of the interacting partners of PARP1 in C. elegans. When affecting one protein, a small molecule might be affecting many others…

The authors have found that PJ34 not only inhibits PARP1, but it also has high affinities for Pim1 (IC50 = 3.7 µM) and Pim2 (IC50 = 16 µM) serine/threonine kinases, which are involved in many of the processes relevant to PARP biology. This result questions the appropriateness of using PJ34 as a chemical tool to probe the biological role of PARP1 and PARP2 at the high micromolar concentrations applied in most studies.

Reference:

Antolín AA, Jalencas X, Yélamos J, Mestres J. Identification of Pim Kinases as Novel Targets for PJ34 with Confounding Effects in PARP Biology. ACS Chem Biol. 2012 Oct 1;

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