Collaborating to combat CF: Structural GenomiX and Cystic Fibrosis Foundation sign screening deal

Structural GenomiX (SGX) recently announced the signing of a three-year, $15-million deal with Bethesda, Md.-based Cystic Fibrosis Foundation Therapeutics (CFFT) to discover novel therapeutics for the treatment of cystic fibrosis, a genetic pulmonary disease that affects nearly 30,000 people in the United States.

Randall C Willis
SAN DIEGO—Structural GenomiX (SGX) recently announced the signing of a three-year, $15-million deal with Bethesda, Md.-based Cystic Fibrosis Foundation Therapeutics (CFFT) to discover novel therapeutics for the treatment of cystic fibrosis, a genetic pulmonary disease that affects nearly 30,000 people in the United States.
 
Under the terms of the agreement, SGX will apply its proprietary FAST Lead Generation Technology to identify new compounds that work to "correct" the delta-F508 form of the cystic fibrosis transmembrane regulator (CFTR) protein, the most common cause of CF. In exchange, CFFT will provide $15 million in technology access, research funding, and milestone payments to SGX, and will be responsible for product development. Should a successful, marketable candidate be found, SGX will also be eligible for clinical development milestone and royalty payments.
 
According to Diana Wetmore, CFFT VP of Alliance Management, the mission of the CF Foundation is to assure the development of the means to cure and control CF and to improve the quality of life for those with the disease. CFFT is the nonprofit drug development affiliate of the CF Foundation that operates drug discovery, development, and evaluation efforts.
 
"The CFFT contracted with SGX nearly five years ago to determine atomic-resolution structures of the CFTR protein, either in whole or in part, with the goal of providing information about how the protein functions," says Dr. Stephen Burley, SGX CSO. "Following on critically important successes that transformed how people think about the molecular mechanism responsible for the disease, we recently expanded the program to employ the SGX fragment-based drug discovery strategy to find drug candidates for CF."
 
SGX's FAST method uses X-ray crystallography to directly screen for small drug-like chemical scaffolds that bind selectively to target proteins. Armed with this structural knowledge, scientists chemically modify the scaffold to improve both potency and selectivity.
 
"Our goal is to produce a small-molecule drug candidate that binds tightly, and preferentially, to the disease-causing form of the CFTR protein and, thereby, correct the underlying molecular defect responsible for the illness," he says. "This approach is unique to SGX, because no other drug discovery company has sufficient bandwidth in X-ray crystallography."
 
Previous research has shown that the delta-F508 mutant form of the CFTR protein is functional, but because of errors in protein folding, it is incapable of reaching the correct location in the cell to perform its function and is instead selectively degraded by the cell's natural machinery. According to Wetmore, CFFT hopes that SGX's method will help identify small-molecule drugs that will bind to the defective protein, stabilizing it in its correct form long enough for it to function correctly.
 
"From basic biophysics, we know that any ligand that binds preferentially to the folded form of a protein versus the unfolded form will stabilize the folded protein," she explains. "Additionally, the binding of such a ligand may lower the energy barrier during the dynamic folding process, allowing folding to take place more rapidly. If the hypothesis that the delta-F mutation destabilizes CFTR in some way that allows it to be flagged for premature degradation is correct, then a ligand that stabilizes delta-F508 CFTR could be a corrector drug."
 
If this works, the question remains open about other possible "corrector" drugs for other disorders involving misfolded proteins, such as the neurodegenerative conditions Alzheimer's disease and Creutzfeld-Jakob Disease.
 
"There is unlikely to be any direct application," says Burley. "Our goal is to find a small-molecule drug that specifically interacts with CFTR protein to overcome (i.e., correct) the molecular defect caused by the delta-F508 mutation. We do, however, believe that lessons learned with CFTR will help guide how best to apply the same technology to other drug discovery targets at the heart of other protein-transport-related diseases."

Randall C Willis

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