Aiming to combat a mutated gene linked to cystic fibrosis, Structural GenomiX Inc. secured a $15 million, three-year agreement with Cystic Fibrosis Foundation Therapeutics Inc.

The agreement comes less than a week after the San Diego-based company received a $48.5 million grant from the National Institutes of Health to discover the 3-dimensional structures of proteins.

Under the collaboration with Bethesda, Md.-based CFFT, the company plans to use its FAST lead generation technology to discover compounds that can correct the delta F508 form of the cystic fibrosis transmembrane regulator protein. The mutation is the one most commonly observed in people with cystic fibrosis.

"The new deal with [CFFT] represents the next step in a relationship that's now nearly 5 years old," said Stephen Burley, chief scientific officer at Structural GenomiX (SGX).

The companies came together in January 2001 to determine the 3-dimensional structures of certain components of the CFTR protein. Not only did they learn that the mutation does not cause the protein to lose its shape, but they characterized the 3-dimensional structure of delta F508.

"It changed the way researchers in the field were thinking about the underlying molecular origin of the disease," Burley told BioWorld Today.

People with the delta F508 mutation cannot transport the CFTR protein to the cell surface, resulting in impaired chloride transport across the lung epithelium. A corrector could help improve breathing, more rapidly clear lung secretions and reduce the chance for lung infections. Currently, the only "viable, corrective therapy" for patients, Burley said, is a lung transplant.

Now in the second stage of research, CFFT plans to potentially provide more than $15 million in technology access, research funding and milestone payments to Structural GenomiX. The milestone payments will be based on the production of small molecules that have the desired biochemical and cellular activity. SGX will work to find molecules that bind to the mutant form of CFTR and will test them for their ability to correct the genetic defect. The goal is to have a preclinical candidate by the end of the three-year agreement. Once at the development stage, "SGX will be eligible for clinical development milestones and royalties on any products that result," Burley said.

Cystic fibrosis (CF) affects about 30,000 people in the U.S. While more than 10 million Americans carry the defective gene that causes CF, it takes two copies of the gene for a child to get the disease. The defective gene causes the body to produce a thick, sticky mucus that results in lung infections and causes pancreatic insufficiency, which impairs digestion. The median age of survival is 35 years.

CF is an indication outside of SGX's main focus. The privately held company primarily works in oncology and recently has launched a registration study for its lead drug Troxatyl in acute myeloid leukemia. It also is in the final stages of a Phase I/II trial of Troxatyl in solid tumors, and it has a variety of kinase inhibitors in preclinical development.

The $48.5 million award received last week from the NIH provides five years of renewed funding for the New York Structural Genomics Research Consortium, which is working to understand the role of proteins in disease in order to design new therapies.

"We're doing a comprehensive study of the protein phosphatases, signal transduction molecules that are involved in cancer, the immune response and metabolic disease," Burley said. "They represent, we believe, another important group of drug discovery targets."

SGX also will work in collaboration with three other centers funded by NIH - the Joint Center for Structural Genomics, the Midwest Center for Structural Genomics and the Northeast Structural Genomics Consortium - to provide structural information for as many gene products as possible. The scientists estimate that there are between 5,000 and 10,000 distinct protein shapes that are used repeatedly in humans, Burley said.

"You can think of the program as a sequel to the human genome project," he said.

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