Calling the X-MAN to battle cancer gene
September 2012
by Jim Cirigliano  |  Email the author


CAMBRIDGE, United Kingdom—Neighboring Cambridge companies in the United Kingdom have announced a partnership to collaborate on a robust lead-optimization oncology program. Domainex has identified a series of lead molecules against TBK1/IKKe—a gene implicated in several forms of cancer—and Horizon Discovery is using a series of isogenic models and assays to further profile the compounds.
Domainex has a long track record in drug discovery involving expression of proteins, designing assays, screening and medicinal chemistry. Horizon brings to the table its sophisticated capabilities in using advanced cell biology to characterize a drug's activity in cancer. Together, they hope to support Domainex's TBK1/IKKe oncology research program, which is being conducted in collaboration with the Institute of Cancer Research (ICR) in London.  
Horizon will provide cell models, phenotypic assays and extensive expertise in highly sophisticated cell biology as it relates to oncology. Horizon's GENESIS genome-editing platform enables researchers to make precise alterations of DNA sequences in human cellular genomes, allowing them to create cell-line models it calls "patients in a test tube." These cell lines—dubbed "X-MAN" cell lines—enable researchers to mimic a "patient" in vitro and screen known cancer genes and pathways under conditions that mirror the microenvironment of the disease.
"Horizon's X-MAN cell-line library now includes more than 450 disease models that accurately model the disease-causing mutations in cancer patients, covering many of the most important activated cancer genes and pathways found in patients, such as BRCA, PI3K, PTEN, p53, B-Raf, K-Ras, Smoothend, MTor, IDH1 and EGFR," says Kam Dhaliwal, director of business development at Horizon.  
Domainex is something of a drug discovery powerhouse, offering drug discovery services to clients and collaborators in addition to its own in-house drug development. The company has developed on behalf of its clients and collaborators, on average, one drug candidate per year during the past five years.
"With such a successful track record, it made sense to invest in its own drug discovery efforts," says Joanne McCudden, Domainex's head of business development.
Domainex's most advanced program is its TBK1/IKKe inhibitor. The drug is promising in applications such as breast and ovarian cancer, among others, but the results of this collaboration will be used to identify which cancers to target first.
IKKe and TBK1 are very closely related enzymes with related, sometimes overlapping,  functions in different types of cells, explains Dr. George Buckley, business development manager at Domainex.  
"Recent academic research has identified the cellular mechanisms by which a drug that is able to inhibit these two protein kinases will be effective in the treatment of cancer, some inflammatory diseases, obesity and type 2 diabetes," Buckley says. "Several independent research groups have shown that IKKe and TBK1 are causative agents in the progression of these target diseases."  
Suppression of these enzymes, such as by RNAi methods, has a positive effect on biomarkers in cell-based assays and in animal models of disease, he adds.
"Domainex has compounds that are potent and selective inhibitors of both IKKe and TBK1, and has shown the expected phenotype in our cellular tests," he says. "Taking together the literature and our own data, we know that by inhibiting IKKe and TBK1 with small-molecule drugs, it is possible to block a number of cell-signaling processes that are associated with disease progression. This intervention will stop progression of the disease. Therefore, the oral drugs which we are inventing will provide patients with a better quality of life and improved long-term health outcomes."  
The therapies derived from this partnership will be the first drugs with activity against TBK1/IKKe, making it a unique and pioneering approach to cancer therapy. Domainex and the ICR have already partnered on the TBK1/IKKe program, among others.  
Domainex commissioned the ICR to perform some studies using Horizon's isogenic cell lines, and now this process is being repeated on a larger scale at Horizon. ICR scientists were the first to observe the potential of Domainex's compounds in cancer.   The partnership between Horizon and Domainex came about because the management teams at each company—being nearby to one another in Cambridge—had long been aware of each other's technologies and expertise. They recognized an opportunity to bring together complementary sets of talents to work toward a common outcome.
"Horizon's oncology and genome editing expertise are a valuable complement to our in-house biochemistry, medicinal chemistry and computer-aided drug design capabilities," Domainex CEO Eddy Littler said in a media release announcing the collaboration. Although this collaboration will focus on oncological applications of the isogenic disease modeling technology—particularly targeting the TBK1/IKKe gene as it relates to various cancers—the same tools can be brought to bear in examining myriad other diseases in the future.
"At this stage, we will be profiling compounds in lead optimizations," says Littler. "In the near future will be the selection of a candidate drug to take into preclinical and clinical studies."  
"The technology can be applied to any disease that is genetically mediated and transcends therapeutic areas," adds Dhaliwal.  
Financial terms of the agreement were not disclosed.
Code: E091207

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