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Graffinity Rides New Chemical Genomics Wave Using Small Molecule Microarrays


First there were DNA microarrays. Then there were protein chips. Now, Graffinity Pharmaceuticals of Heidelberg, Germany, is using microarrays with small molecule drug-like compounds to provide drug target screening services for pharmaceutical and biotech companies.

In the emerging field of chemical genomics, these new arrays promise to provide an alternative to high-throughput screening for ligands that bind to potential protein drug targets. A number of academic groups, most notably Stuart Schreiber’s at Harvard University, have developed chemical microarrays. But Graffinity claims to be the first and only company to use these chips for commercial services.

Graffinity’s three founders, Dirk Vetter, Kristina Schmidt, and Holger Ottleben, met at Jena University in the late 1990s and decided to “develop something really novel that, in our opinion, would be an excellent tool for drug discovery,” said Ottleben, the company’s vice president of scientific strategy. Vetter brought microarray experience from a prior position at Affymax, which later spun off Affymetrix. The trio started Graffinity in Jena in late 1997 with 125,000 ($111,000) in seed funding from the Technologie-Beteiligungs-Gesellschaft, a venture capital and consulting subsidiary of the bank Deutsche Ausgleichsbank.

Since then, the company has raised nearly 36 million ($31 million) in venture financing, has grown to 94 employees, and moved into 2,000 square meters of lab space near the Heidelberg University campus. The company is hoping to expand even more this summer, with an additional 3,000 square meters currently under construction.


Molecules on Gold


Graffinity’s chips consist of glass covered with a layer of gold and an organic self-assembling monolayer. The company put a lot of effort into optimizing the surface chemistry to prevent non-specific protein binding, said Ottleben. The monolayer allows a library of pre-synthesized organic compounds to be attached covalently — and with defined spacing and density — to the surface of the chip.

The company makes the compounds that it will attach to its chips using parallel combinatorial synthesis. Each compound contains a tag by which it is attached to the chip, and every batch provides enough material to manufacture 1,000 identical chips, each harboring 4,608 compounds on the footprint of a microtiter plate. Graffinity’s in-house library currently contains about 100,000 compounds but is rapidly growing: “We will have 250,000 by the end of the year,” said Ottleben.

On chemical arrays, assays for protein binding are function-blind and label-free: Graffinity has developed a surface plasmon resonance imaging device that illuminates the chip from the bottom and projects the reflected light on a CCD camera. The technique involves measuring a change in refractive index upon protein binding. Results provide a “semi-quantitative binding profile against all compounds on the array,” including weak affinity binders, said Ottleben.

The company has used the technology to screen almost 100 different proteins, including enzymes, nuclear receptors, single-chain membrane proteins, and various receptor and interaction domains, but not ion channels. It currently operates on a fee-for-service partnership model and counts a number of pharmaceutical and biotechnology companies among its clients. Last year Graffinity announced promising results from screens for Aventis Pharma and Celera. “They have been extremely pleased with the quality of the data that we delivered. This is something we are pretty proud of,” said Ottleben.

In the immediate future, Graffinity wants to place more emphasis on medicinal chemistry in order to provide clients with optimized leads. Last month, the company hired as its vice president of R&D Victor Matassa, who most recently served as director of medicinal chemistry-Europe at Eli Lilly.

In the future, Graffinity wants to do more in-house discovery. “We will make our profits, in the long run, on outlicensing lead compounds,” said Ottleben.

But now, even though no other company offers chip-based screening of small molecule libraries, Graffinity has to contend with others that offer more traditional liquid-phase high-throughput screening or libraries, like ComGenex, Evotec OAI, or Neogenesis.

The main advantage of microarrays over these techniques lies in their high density — they require very little material both in terms of the compound library and protein samples. Also they are addressable in space, greatly simplifying compound identification. But some experts are doubtful about the stability of the molecules on the chip, and others point out the low number of compounds in Graffinity’s library. “In one synthesis, we make millions of compounds,” says Kit Lam, professor of medicine at the University of California, Davis. He uses a bead-based screening approach in liquid phase to determine protein ligands, then applies chemical microarrays to characterize subsets of those.

Michael Foley, vice president of chemical technology at Infinity Pharmaceuticals, is more concerned about the nature of chemical libraries than about the assay format—chips or liquid phase. “The current collection of molecules is fundamentally flawed,” lacking in diversity and stereochemical complexity, he said. Foley wants to focus on making “large collections of molecules that have structural features that are more reminiscent of natural products,” and intends to use his own chemical microarrays, based on Schreiber’s technology, for in-house screens. “It’s just one tool,” he commented, “and we don’t rate that tool as any more or less important than any other technology for screening molecules.”

— JK

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