Calling the X-MAN to battle cancer gene

CAMBRIDGE, United Kingdom—Neighboring Cambridge companies inthe United Kingdom have announced a partnership to collaborate on a robustlead-optimization oncology program. Domainex has identified a series of leadmolecules against TBK1/IKKe—a gene implicated in several forms of cancer—andHorizon Discovery is using a series of isogenic models and assays to furtherprofile the compounds.

Domainex has a long track record in drug discovery involvingexpression of proteins, designing assays, screening and medicinal chemistry.Horizon brings to the table its sophisticated capabilities in using advancedcell biology to characterize a drug's activity in cancer. Together, they hopeto support Domainex's TBK1/IKKe oncology research program, which is beingconducted in collaboration with the Institute of Cancer Research (ICR) in London.

Horizon will provide cell models, phenotypic assays andextensive expertise in highly sophisticated cell biology as it relates tooncology. Horizon's GENESIS genome-editing platform enables researchers to makeprecise alterations of DNA sequences in human cellular genomes, allowing themto create cell-line models it calls "patients in a test tube." These celllines—dubbed "X-MAN" cell lines—enable researchers to mimic a "patient" invitro and screen known cancer genes andpathways under conditions that mirror the microenvironment of the disease.

"Horizon's X-MAN cell-line library now includes more than450 disease models that accurately model the disease-causing mutations incancer patients, covering many of the most important activated cancer genes andpathways found in patients, such as BRCA, PI3K, PTEN, p53, B-Raf, K-Ras,Smoothend, MTor, IDH1 and EGFR," says Kam Dhaliwal, director of businessdevelopment at Horizon.

Domainex is something of a drug discovery powerhouse,offering drug discovery services to clients and collaborators in addition toits own in-house drug development. The company has developed on behalf of itsclients and collaborators, on average, one drug candidate per year during thepast five years.

"With such a successful track record, it made sense toinvest in its own drug discovery efforts," says Joanne McCudden, Domainex'shead 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, amongothers, but the results of this collaboration will be used to identify whichcancers to target first.

IKKe and TBK1 are very closely related enzymes with related,sometimes overlapping, functionsin different types of cells, explains Dr. George Buckley, business developmentmanager at Domainex.

"Recent academic research has identified the cellularmechanisms by which a drug that is able to inhibit these two protein kinaseswill be effective in the treatment of cancer, some inflammatory diseases,obesity and type 2 diabetes," Buckley says. "Several independent researchgroups have shown that IKKe and TBK1 are causative agents in the progression ofthese target diseases."

Suppression of these enzymes, such as by RNAi methods, has apositive effect on biomarkers in cell-based assays and in animal models ofdisease, he adds.

"Domainex has compounds that are potent and selectiveinhibitors of both IKKe and TBK1, and has shown the expected phenotype in ourcellular tests," he says. "Taking together the literature and our own data, weknow that by inhibiting IKKe and TBK1 with small-molecule drugs, it is possibleto block a number of cell-signaling processes that are associated with diseaseprogression. This intervention will stop progression of the disease. Therefore,the oral drugs which we are inventing will provide patients with a betterquality of life and improved long-term health outcomes."

The therapies derived from this partnership will be thefirst drugs with activity against TBK1/IKKe, making it a unique and pioneeringapproach to cancer therapy. Domainex and the ICR have already partnered on theTBK1/IKKe program, among others.

Domainex commissioned the ICR to perform some studies usingHorizon's isogenic cell lines, and now this process is being repeated on alarger scale at Horizon. ICR scientists were the first to observe the potentialof Domainex's compounds in cancer.

The partnership between Horizon and Domainex came aboutbecause the management teams at each company—being nearby to one another inCambridge—had long been aware of each other's technologies and expertise. Theyrecognized an opportunity to bring together complementary sets of talents towork toward a common outcome.

"Horizon's oncology and genome editing expertise are avaluable complement to our in-house biochemistry, medicinal chemistry andcomputer-aided drug design capabilities," Domainex CEO Eddy Littler said in amedia release announcing the collaboration.

Although this collaboration will focus on oncological applicationsof the isogenic disease modeling technology—particularly targeting theTBK1/IKKe gene as it relates to various cancers—the same tools can be broughtto bear in examining myriad other diseases in the future.

"At this stage, we will be profiling compounds in leadoptimizations," says Littler. "In the near future will be the selection of acandidate drug to take into preclinical and clinical studies."

"The technology can be applied to any disease that isgenetically mediated and transcends therapeutic areas," adds Dhaliwal.

Financial terms of the agreement were not disclosed.