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Going after GPCR
CAMBRIDGE, Mass.—Anchor Therapeutics has entered into a collaborative agreement with Kyowa Hakko Kirin Co. Ltd. (KHK) to utilize Anchor's proprietary pepducin technology to advance KHK's internal G protein-coupled receptor (GPCR) drug discovery portfolio.
The agreement with KHK takes advantage of Anchor's recently adopted business strategy to offer its pepducin technology for use as in-vitro and in-vivo research tools, in addition to developing pepducin therapeutics on its own. Under the agreement, Anchor and KHK will work jointly to discover and optimize pepducin research tools to further the molecular understanding of certain GPCR targets in the KHK portfolio. KHK will assume responsibility for application of the research tools against the targets. Anchor will receive an upfront payment, research funding and downstream milestones.
Pepducins were first developed at the Tufts Medical Center laboratories. They utilize lipidated fragments of intracellular GPCR loops to modulate GPCR action in targeted cell-signaling pathways. Anchor licensed its foundational intellectual property from Tufts Medical Center and commenced operations in early 2008 to advance pepducin therapeutics and research tools, notes Dr. Thomas J. McMurry, senior vice president of R&D and interim president of Anchor.
"Our novel pepducin lipopeptides are designed to allosterically modulate internal cell signaling via specific interactions with intracellular GPCR domains," he says. "We are exploiting the power of this unique mechanism to develop research tools to help unlock GPCR pharmacology as well as to discover new therapeutics."
The company's semivirtual operations are based in Cambridge, Mass., and comprise "a core scientific staff of four and a network of consultants and CRO partners," McMurry states. He adds that the company has no plan to recruit a full-time president.
"The licensing of pepducin technology is a fundamental component of our business strategy, and we are actively pursuing other collaborations with pharmaceutical and biotechnology companies and research institutions," he says.
Pepducins are novel, allosteric modulators for GPCR targets, especially those intractable to current approaches. They are composed of a short peptide derived from a GPCR intracellular loop linked to a lipid moiety. This structure allows pepducins to anchor in the cell membrane and target the GPCR protein via a unique intracellular allosteric mechanism.
"Drugs can interact with a GPCR target receptor at different locations," McMurry observes. "Traditionally, most drugs have been designed to interact with the same binding site as used by the receptor's natural activating ligand. One relevant example is Novo Nordisk's Victoza—an approved lipopeptide drug that binds the orthosteric GLP-1 binding site."
Allosteric drugs interact with the targeted receptor at a different binding site than that used by the natural ligand, he explains. Because allosteric compounds do not directly compete with the endogenous ligand for the same binding site, a "Negative Allosteric Modulator" (NAM) can block signaling even in the presence of high concentrations of the natural ligand. In case of aberrant natural signaling, the NAM approach provides a safe and effective mechanism to suppress the undesired signaling. Conversely, in therapeutic situations where one would like to gently enhance the positive activity of an endogenous ligand, a "Positive Allosteric Modulator" is the pharmacology of choice. This mechanism enhances the activity of the natural ligand without overstimulation of the receptor that might lead to undesired side effects. Anchor has also demonstrated that its pepducin modulators are capable of biased signaling—the ability to selectively influence certain downstream signaling pathways but not others. Biased ligands represent an additional exciting opportunity for generating therapeutics with improved efficacy and safety profiles, McMurry adds.
The Anchor pepducin technology platform represents "an entirely new paradigm for modulating GPCR signal transduction, potentially providing a novel approach to studying the in-vitro and in-vivo biology of GPCRs and screening for small-molecule modulators of these targets," McMurry claims. He says he believes the technology may transform the scope of GPCR therapeutics to treat a much wider range of serious illnesses, including inflammatory and metabolic diseases.
KHK is a leading biopharmaceutical company in Japan. It had a new start in October 2008 following the merger of Kyowa Hakko Kogyo Co. Ltd. and Kirin Pharma Company Ltd., with the aim of becoming a global specialty pharmaceutical company that creates innovative new drugs in its core business areas of oncology, nephrology and immunology.