Compounds that inhibit an enzyme, VCP, by using one of three mechanisms provide new tools to combat cancer, according to a paper published online this week 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. VCP has also been increasingly linked to cancer, where its function is necessary to maintain the health of cancer cells. Inhibition of VCP function should therefore prevent normal protein degradation and cause buildup of undesired sequences, leading to death of cancer cells.
Paola Magnaghi and colleagues report a suite of synthetic compounds that inhibit VCP by three different mechanisms. One group of compounds binds to the same site as ATP, similar to known VCP inhibitors, which are not selective for this protein. However, two groups of compounds work in new ways: one group forms a covalent bond to the protein within the ATP site, while a final group binds to an unexpected allosteric site away from the ATP site, likely shutting down protein function by preventing conformational changes needed for catalysis. The team reports that these two groups, represented by the compounds NMS-859 and NMS-873, were able to cause cell death in a number of cancer cell lines.