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. “Our technology reverses that, and we screen one compound against thousands of proteins at one time,“ 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% of the proteome, they represent about 40% of all druggable targets. “We screen against this extremely important part of the human proteome,“ 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. “Companies have become incredibly interested in HSP-90 as a target in the last six months,“ 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´ chemo-proteome technology not only confirmed that Geldanamycin targets HSP-90 but it also discovered a second target, ADE2, a major contributor to Geldanamycin´s 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.
“We discovered through our chemo-proteomics platform completely novel molecules unrelated to Geldanamycin,“ 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. “We have one of the best, if not the best, HSP-90 program in the industry,“ 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´s 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. “By 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,“ says Kent.