(PHILADELPHIA) – Combining natural organic atoms with metal complexes, scientists at The Wistar Institute have developed a new type of enzyme inhibitor capable of blocking a biochemical pathway that plays a key role in cancer development.

Based on studies in human melanoma cells, the research paves the way for developing new ways to treat cancer by dampening the overactive enzyme activity that leads to uncontrolled tumor growth.

Details of the study, to be published in the May 16 issue of the journal ACS Chemical Biology, show how small-molecule inhibitors can be designed to target a family of signaling proteins, called phosphatidyl-inositol-3-kinases, or PI3Ks.

By teasing out the three-dimensional structure of an enzyme complex involved in a variety of cell signaling pathways, a team of researchers has exposed how one of the genes most commonly mutated in human cancers helps good cells go bad.

The structure, described in the December 14, 2007, edition of the journal Science, should help scientists design new drugs to fight certain cancers, including those of the colon, liver, breast, and ovary.

“Structures always have some intrinsic beauty and interest on their own, but the reason we're particularly interested in this protein is because the gene that encodes it is very commonly mutated in human cancers.”
Bert Vogelstein

    The compound, XL418 is an inhibitor of protein kinase B (PKB or AKT) and S6 Kinase (S6K), key components of the phosphoinosotide-3 kinase (PI3K) signaling pathway. Activation of these kinases is a frequent event in human tumors, promoting cell growth, survival and resistance to chemotherapyterm and radiotherapy.

   "One of our drug development strategies is to systematically target key nodes in signaling pathways that are frequently deregulated in human tumors. An important component of this strategy is our focus on signaling downstream of PI3K," said Gisela Schwab, senior vice president at Exelixis.

 Semafore Pharmaceuticals, Inc. today announced receipt of a grant award from the Multiple Myeloma Research Foundation (MMRF) for a Phase l trial evaluating its Pl3K inhibitor SF1126 in multiple myeloma.

This is the second clinical trial grant awarded to Semafore-last week the company announced receipt of a grant from Cancer Treatment Research Foundation (CTRF) to help fund a Phase l trial of SF1126 in solid cancers.

Both Phase l trials are expected to commence in 2007. Separately, Semafore announced that multiple myeloma preclinical studies sponsored by the company and its collaborators at Emory University have been selected for an oral presentation at the upcoming 48th Annual Meeting of the American Society of Hematology (ASH.) "This generous grant from the MMRF will enable us to rapidly initiate a clinical trial of SF1126 in multiple myeloma," said Dr. Joseph Garlich, president and chief scientist of Semafore. "The MMRF has an outstanding track record of funding innovative research that has significantly increased the treatment options available to myeloma patients.