Developing effective drugs against important targets involves more than rapid sequencing and small molecule libraries: studies of protein structure and function continue to form the backbone of careful characterizations of the workings of cells. Caspases, a family of about a dozen cysteine proteases in cells that is central to apoptosis, or programmed cell death, illustrate how companies are elucidating the biology of a pathway to develop treatments for disease.

According to John Reed, scientific director of the Burnham Institute (La Jolla, Calif.), apoptosis has been implicated in more than 70 percent of major illnesses for which cures have not been found. The apoptotic process, which is characterized by a set of morphological changes that cells undergo during programmed death, is now widely believed to require caspase activation.

Moreover, as enzymes, caspases make good targets for small molecules, and can be inhibited to reduce damage from stroke or myocardial infarction or induced to treat cancer.

Three companies - Idun Pharmaceuticals Inc. (San Diego, Calif.), Merck & Co. Inc. (MRK, Whitehouse Station, N.J.) and Vertex Pharmaceuticals Inc. (VRTX, Cambridge, Mass.) - have broad, significant programs in caspase research.

Idun's initial focus is on broad spectrum caspase inhibitors to treat acute indications such as stroke. Idun also has programs investigating the use of caspases in chronic conditions such as neurodegenerative diseases and cancer. MRK has caspase projects in acute indications such as sepsis as well as chronic indications such as neurodegeneration. VRTX initially has targeted inflammatory conditions.

Among other players, Maxim Pharmaceuticals Inc. (MAXM, San Diego, Calif.) uses high throughput screening to identify compounds that inhibit or induce caspases and has identified broad spectrum caspase inhibitors as well as specific inducers of apoptosis in certain cancers. Maxia Pharmaceuticals Inc. (San Diego, Calif.) has identified molecules that act though caspases to induce apoptosis in cancer.

The caspase family

Caspases float inside cells as inactive proenzymes until they are cut by other molecules, including upstream caspases. When activated, caspases cleave other molecules in cells, such as cytoskeletal proteins, to begin the programmed cell death process. According to an October 2000 article in Nature Insight by Michael Hengartner of Cold Spring Harbor Laboratory, caspases appear to destroy a restricted set of proteins in cells that are associated with the morphological changes characteristic of apoptosis. For example, caspases cleave nuclear lamins, which causes the cell nucleus to shrink.