by ecancer reporter Janet Fricker

Compounds that inhibit an enzyme, VCP, through one of three mechanisms have the potential to provide new approaches to combat cancer, reports a paper published online in Nature Chemical Biology.

VCP, also known as p97 or Cdc48, is an ATPase (an enzyme that uses energy from breakdown of ATP to complete other reactions), that plays a role in the controlled degradation of proteins. It is known to have an essential biological role, demonstrated by the embryonic lethality of ‘knock-out’ mice and by syndromes linked to VCP mutations.

The late onset of such genetic disorders has suggested that partial loss of VCP function could be tolerated for prolonged periods.

VCP has also been linked to cancer, where its function is thought to be necessary to maintain the health of cancer cells.

Inhibition of VCP function, reason Paola Magnaghi and colleagues, from Nerviano Medical Sciences, Nerviano, Italy, might prevent normal protein degradation and cause the build up of undesired sequences, resulting in the death of cancer cells. In the current study the group conducted high-throughput screening (involving a one million compound library)on recombinant VCP to identify three groups of small molecules that could target its ATPase activity.

One group of compounds bound to the same site as ATP, similar to known VCP inhibitors, which are not selective for this protein.

The other two groups of compounds however, work in different ways.

One group forms a covalent bond to the protein within the ATP site; while the second binds to an unexpected allosteric site away from the ATP site, and is likely to work by shutting down protein function by preventing conformational changes needed for catalysis.

Using these compounds the team then analysed the effects of VCP silencing on the growth, cell cycle profile and cellular pathways in different cancer cells lines.

Two of the groups, report the investigators, were able to cause cell death in a number of cancer cell lines.

The results, they believe, suggest that the possibility of targeting VCP might prevent proteasome inhibitor-resistant tumours from escaping through the aggresome autophagy pathways and cause them to collapse under the high load of unfolded proteins.

“In conclusion, we identified different classes of VCP-targeting compounds, showing that VCP is a druggable target by multiple mechanisms, including a new allosteric mechanism,” write the authors.

Reference

P Magnaghi, R D’Alessio, B Valsasina, et al. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Published online: 28 July2013 doi: 0.1038/nchembio.1313