Dermatology is sometimes derided as a vanity-driven medical field, with the dermatologist seen as an examiner of acne while heart surgeons save lives.

But beyond skin cancer, which dermatologists deal with, there also is pemphigus vulgaris, which has nothing to do with helping people to look like supermodels: In bad cases of the blistering skin disease, which is caused by autoantibodies to the cell-cell adhesion molecule dsg-3, the victim's skin basically falls off.

With the advent of steroids and immunosuppressants, the disease usually is no longer fatal. Unfortunately, the side effects of the medications still can be, which makes the discovery and development of targeted treatments a high-priority item.

A paper in the Aug. 22, 2006, issue of the Proceedings of the National Academy of Sciences showed that inhibition of p38 MAP kinase might be useful in the fight against pemphigus vulgaris.

Senior author David Rubenstein, an associate professor of dermatology at the University of North Carolina at Chapel Hill, said that given his team's previous work, the findings are "logical, but nevertheless very exciting to us, because they suggest that the inhibitors that are being developed for inflammatory joint diseases might turn out to be extraordinarily useful for the treatment of pemphigus vulgaris."

In the work reported in PNAS, Rubenstein and his team transferred dsg-3 autoantibodies from patients into mice, which then developed the skin disease. Rubenstein emphasized that from the point of view of the mouse, the process is passive: "There is no active immune response," allowing the scientists to specifically assess the effects of the autoantibodies as opposed to other components of the immune system.

Using that model, Rubenstein's team previously had shown that p38 MAP kinase is activated after exposure to dsg-3 autoantibodies, as is the heat-shock protein HSP-27. In the new paper, the scientists showed that inhibiting p38 MAP kinase prevented the formation of blisters. The inhibitors did not prevent the binding of the autoantibody to skin cells; instead, it appeared to block the loss of cell-cell adhesion that occurs as p38 MAP kinase phosphorylates HSP-27, which in turn alters the cytoskeleton.

Rubenstein said he hopes the model will aid in the development of treatments that are targeted directly at p38 MAP kinase.

Of course, that kinase has proved an extremely challenging target so far. Lew Shuster, CEO of privately owned San Diego firm Kemia Inc., recently told BioWorld Today that of 17 drug hopefuls targeting p38 MAP kinase, none have even made it into Phase III, let alone to an NDA filing or approval. The reason, Shuster said, was that most drugs aimed at p38 target the kinase's ATP binding pocket, which makes them nonselective. Because there are so many proteins in the body that interact with ATP, it's hard to make a drug selective for only p38 MAP kinase and not the ATP-binding pocket, he said. (See BioWorld Today, August 24, 2006.)

But that doesn't seem to have deterred further drug development efforts. Kemia, for one, recently reported positive Phase I data with an allosteric inhibitor of p38 MAP kinase for treating rheumatoid arthritis. And Rubenstein's group already is in discussions with several biotechnology and pharmaceutical firms that want to test such inhibitors in the pemphigus vulgaris model.