Chemo-Proteomics Approach to Cancer

April 15, 2006 (Vol. 26, No. 8)

Serenex’ Platform Looks at Complex Interactions & Multiple Targets Simultaneously

Many biopharmaceutical companies are seeking new anticancer treatments. Serenex (www.serenex.com) is among them. Its lead compound, SNX-1012, is a first-in-class therapy for oral mucositis, the most common debilitating side effect of chemotherapy and radiation treatments for solid tumors. SNX-1012 blocks multiple inflammatory and other key pathways involved in oral mucositis.

Nearly half a million patients develop oral mucositis yearly, resulting in inflammation and ulceration of the mouth and throat tissue. &#8220Oral mucositis is not just a sore mouth,&#8220 stresses Richard Kent, M.D., president and CEO. The New England Journal of Medicine published a poem in 1990 by a patient suffering from oral mucositis who described the condition as &#8220a fish hook lodges in my throat&#8220 and &#8220coiled steel razored wire atop dentate prison walls.&#8220 SNX-1012, applied as a mouth rinse, may reduce such symptoms.

Severe cases of oral mucositis require hospitalization, intravenous nutrition, and narcotic pain control. Oral mucositis also may progress to bacteremia and sepsis, causing death. A serious consequence of oral mucositis is the interruption of radiation and chemotherapy, which diminishes the efficacy of these treatments.

There is no approved treatment for oral mucositis for patients with solid tumors, and a successful product could earn $1 billion annually. &#8220Oral mucositis is a large under-appreciated medical problem and commercial opportunity,&#8220 says Dr. Kent. Serenex in-licensed worldwide rights to develop and commercialize SNX-1012 from Mucosal Therapeutics, a Biomodels affiliate (www.biomodels.com).

Medical experts previously assumed that oral mucositis occurred when chemotherapy and radiation killed rapidly dividing epithelial cells in the lining of the mouth. Recent evidence shows that multiple tissues and pathways are affected and that oral mucositis starts in the subdermal layers of the oral cavity. SNX-1012 inhibits many of the pathways activated in oral mucositis. &#8220We&#180re working to determine precisely which pathways SNX-1012 interferes with to promote healing of the oral mucosa,&#8220 says Dr. Kent.

Four Phase I trials, including one in patients receiving stem cell transplants, conducted at the Fred Hutchinson Cancer Center in Seattle, showed an excellent safety profile and hinted at a strong pharmacological action. SNX-1012 also &#8220works spectacularly well in animal models of oral mucositis,&#8220 says Dr. Kent. A Phase II trial involving about 30 sites will start in June 2006.

Chemo-Proteome Mining

In addition to its in-licensing program, Serenex discovers lead compounds with its chemo-proteomics platform. Based on affinity binding and proteome mining methods, the platform examines the complex interactions among compounds and multiple targets simultaneously. The technology finds compounds that affect entire families of proteins.

Traditional high-throughput platforms screen millions of compounds against one target. &#8220Our technology reverses that, and we screen one compound against thousands of proteins at one time,&#8220 explains Dr. Kent. The entire process is done in a parallel format that allows the screening of more than a thousand compounds daily.

Serenex was founded in 2001 to advance this chemo-proteomics technology, discovered by Tim Haystead, Ph.D., an expert on protein kinases at Duke University. Serenex uses the platform to target the purine-binding superfamily of proteins that rely on ATP, ADP, FAD, and NAD as co-factors. This superfamily covers about 2,000 proteins, including kinases, heat shock proteins, RNA and DNA processing enzymes, and a large number of metabolic enzymes.

Although the purine-binding proteins make up just 4&#37 of the proteome, they represent about 40&#37 of all druggable targets. &#8220We screen against this extremely important part of the human proteome,&#8220 asserts Dr. Kent.

The chemo-proteomic platform identified SNX-2112 as an inhibitor of heat shock protein 90 (HSP-90), a molecular chaperone protein that regulates the folding and degradation of key signaling molecules in cells. In tumor cells, HSP-90 controls multiple oncogenic proteins, such as Her2 and Raf, and their downstream signaling molecules, such as Akt and Erk, which promote the growth and survival of tumors. Drugs like SNX-2112 could disrupt the growth of a wide range of cancer cells in solid tumors and blood-based cancers. &#8220Companies have become incredibly interested in HSP-90 as a target in the last six months,&#8220 says Kent.

The grandfather HSP-90 inhibitor is Geldanamycin, a natural compound that inhibits the growth of cancerous cells in culture. Several companies have analogs of Geldanamycin in their pipelines. Most Geldanamycin analogs, however, are large, water-insoluble, toxic, and must be administered intravenously. Serenex&#180 chemo-proteome technology not only confirmed that Geldanamycin targets HSP-90 but it also discovered a second target, ADE2, a major contributor to Geldanamycin&#180s toxicity. From 62 analogs of Geldanamycin, Serenex researchers identified specific analogs that display selective inhibition of HSP-90 and antitumor activity, as well as greatly reduced general toxicity.

&#8220We discovered through our chemo-proteomics platform completely novel molecules unrelated to Geldanamycin,&#8220 states Dr. Kent. Serenex filed patents on SNX-2112 and the library of related compounds, which are small, water-soluble, orally bioavailable, very potent, and easy to synthesize. &#8220We have one of the best, if not the best, HSP-90 program in the industry,&#8220 stresses Kent. In September 2005, the company raised $30 million in C-Round financing to fund the development of its HSP-90 inhibitor program and move SNX-1012 through Phase II trials.

A second compound discovered with the chemo-proteomics platform, SNX-2323, targets the cytoskeleton of tumor cells and is in the early optimization stage. Serenex also extends its chemo-proteomics platform to other pharmaceutical and biotechnology companies through selective collaborations.

The company&#180s business plan combines the in-licensing of key compounds like SNX-1012 and an internal discovery group of chemists and biologists who identify and test lead candidates like SNX-2112 and SNX-2323. Moreover, Serenex is in advanced negotiations to in-license a second cancer supportive care compound that protects bone marrow during chemotherapy. &#8220By early 2007, we plan to have two compounds for oncology supportive care in Phase II trials and our HSP-90 inhibitor in Phase I trials,&#8220 says Kent.