Novel targets for new PARP-1 inhibitors
Researchers capture a major chemotherapeutic target in complex with DNA damage
- Date : 16 May 2012
- Topic : Personalised medicine
A new study published in Science May 11 is shedding a light on the molecular details of PARP-1. The investigation led by John Pascal, PhD, an assistant professor in the Department of Biochemistry and Molecular Biology at Thomas Jefferson University and Jefferson's Kimmel Cancer Center, revealed new target sites—including specialized "zinc finger" domains—for PARP-1 inhibitors. The idea for this area of research is to identify more specific PARP-1 inhibitors that achieve a targeted inhibition, with less potential for side effects.
The researchers wanted to define a structural and mechanistic framework to better understand how to specifically inhibit PARP-1. The weak points were found to be multi-domain interfaces that are uniquely found in PARP-1. What researchers now know is that multiple domains of PARP-1 come together and bind to DNA damage, and this "communication" between domains is essential for DNA damage-dependent PARP-1 activity.
DNA damage-dependent PARP-1 activity
PARP-1 is a protein that detects and responds to breaks in the structure of DNA. If PARP-1 activity is impaired, DNA strand breaks are not repaired. In normal tissue, a repair mechanism called homologous recombination fixes the damaged DNA. However, in cancers that carry the BRCA mutation, like certain breast and ovarian cancers, homologous recombination is inactivated. Therefore, the cancerous cells have become dependent on the role PARP-1 plays in DNA repair.
In a more general scenario, inhibiting PARP‑1 has been successful when combined with DNA‑damaging drugs because it enhances the apoptotic activity of these drugs.
Today, many PARP-1 inhibitors being tested in preclinical and clinical studies target the catalytic active site. But this approach is limiting because the catalytic site is similar to those found in other PARP-like proteins that carry out other essential cellular functions, thus increasing the potential for off target side effects.
A major step in understanding an enzyme essential for regulation of cell proliferation and a promising target for cancer therapeutics
Using X-ray crystallography, researchers studied the interaction amongst the component domains of PARP-1 and their combined role in binding to DNA damage. The PARP-1/DNA structure revealed a network of interdomain contacts formed upon DNA binding. These domains have to come together and assemble, the researchers found, to have catalytic activity.
The researchers concluded that their work indicates that they should be looking for inhibitors that prevent these domains from coming together. Rather than screen for inhibitors with catalytic activity as a readout, they can screen for inhibitors that disrupt the communication between the PARP-1 domains, which would in turn shut down catalytic activity. Closer attention to these specialized domains could inspire the design of a new class of PARP inhibitors.
This work was supported by funds from the National Institutes of Health, the American Cancer Society, and the Kimmel Cancer Center X-ray Crystallography and Molecular Characterization Facility at Thomas Jefferson University.
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