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March 21, 2011
Volume 89, Number 12
pp. 18 - 19

Betting On Boron

Case study #2: Naeja helps Anacor realize its goal of boron-containing pharmaceuticals

Michael McCoy

BIG TEAM Hernandez, front row, fifth from left, poses during a research meeting at Naeja’s headquarters. Anacor
BIG TEAM Hernandez, front row, fifth from left, poses during a research meeting at Naeja’s headquarters.
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Despite the ubiquity of boron in Earth’s crust, the element shows up in only one prescription drug: a multiple myeloma treatment marketed by Millennium Pharmaceuticals as Velcade.

Anacor Pharmaceuticals is out to change that. The Palo Alto, Calif.-based biotechnology company is developing a family of boron-containing small-molecule drugs. And with the assistance of Naeja Pharmaceutical, a Canadian contract research organization, Anacor has licensed one of those molecules to GlaxoSmithKline and taken another one into Phase III clinical trials.

Anacor was founded in 2002 to develop technology created by Lucy Shapiro, a Stanford University bacterial geneticist, and Stephen J. Benkovic, a Pennsylvania State University organic chemist. Through a long-standing scientific collaboration, the two researchers had discovered boron-containing compounds that inhibited specific bacterial targets.

Most organic chemists know boron as a component of reagents used in Suzuki coupling reactions to form carbon-carbon bonds. In such reactions, boron is not part of the final product.

“Anacor is interested in keeping that boron in the final compound,” says Vincent Hernandez, who joined Anacor in 2005 as a bench scientist and is now the firm’s director of medicinal chemistry. Boron generally forms three bonds to pair up the three electrons in its outer shell. But boron also has an empty p orbital that can form a fourth bond, known as a dative or coordinate covalent bond. When interacting with targets, such bonds offer greater stability than the noncovalent interactions of most pharmaceuticals. They are particularly useful in enzyme inhibition, Hernandez says.

In fact, Velcade, an aliphatic boronic acid, inhibits protease enzymes. Aliphatic boronic acids, though, typically don’t make good drugs. “Most of them have a metabolic liability where they are readily oxidatively cleaved,” Hernandez says. “They also tend to have rather poor solubility characteristics.”

Anacor’s work-around was a family of cyclic boronic esters known as benzoxaboroles. The firm discovered the esters about eight years ago under a $22 million Department of Defense contract to explore the use of boron chemistry against biowarfare agents such as anthrax. Because of their cyclic element, benzoxaboroles have improved solubility and better metabolic stability, Hernandez says.

It was while working under the defense contract that Anacor hired Naeja to assist the two chemists on its staff. At the time, Naeja was a three-year-old contract research firm run by Ronald Micetich and his son Christopher. Based in Edmonton, Alberta, the firm is staffed by chemists and biologists from a variety of nations who have found Canada welcoming to highly educated immigrants. About three-quarters of its staff are chemists, and almost all have Ph.D.s.

Christopher Micetich, now president of Naeja, recalls that his scientists tackled the Anacor job with gusto. Company chemists helped discover the benzoxaborole scaffold, which led to the discovery of AN2690, an antifungal now being developed to treat onychomycosis, an infection of the toenail. In 2005, AN2690 became the first of Anacor’s five boron-containing compounds to enter clinical trials.


Given the collaboration’s success with the first scaffold, it’s no surprise that Anacor hired Naeja again a few years later. By then Hernandez was on board, and he and his colleagues were trying to figure out what made AN2690 work. Anacor’s discovery biology group, led by Dickon Alley, identified the compound’s target, an enzyme called leucyl-tRNA synthetase, or LeuRS. Then, working with Stephen Cusack at the European Molecular Biology Laboratory in Grenoble, France, Anacor scientists solved the cocrystal structure of AN2690 bound to LeuRS from either bacteria or fungi.

“It was when we got that crystal structure that we really understood how the compound works,” Hernandez says. “It’s probably no surprise that it’s through the reactive p orbital.”

AN2690 is a potent antifungal that doesn’t inhibit bacteria, and the crystal structure showed that this was because the compound wasn’t reaching a key binding site on bacterial LeuRS. Analogs of AN2690 that bound there as well, the Anacor team reasoned, would have the potential to inhibit bacteria instead of fungi. “That was the beginning of a structure-based drug design program,” Hernandez says.

It was Hernandez himself who discovered the breakthrough AN2690 derivative, known as ABX. Subsequent preclinical results formed the basis of the GSK collaboration. In October 2007, the pair signed a boron-based anti-infective medicines deal worth $12 million up front to Anacor and as much as $331 million in milestone payments for each product candidate.

Anacor brought in Naeja to optimize ABX. Once again, Micetich says, Naeja’s medicinal chemists did the job, helping discover a new molecule, AN3365, with the aid of X-ray crystallography and computer modeling. Naeja also contributed to process chemistry. The chemists followed their original “medchem” synthesis, which used chiral high-performance liquid chromatography, with a gram-scale synthesis based on diastereomeric salt resolution. According to Hernandez, Anacor later transferred the Naeja process to contract manufacturer Regis Technologies for Phase I clinical trial production with only minor modifications.

The payoff for all of the work was a licensing deal with GSK. Last July, the British firm paid Anacor $15 million and exercised its option to take over development of AN3365. David J. Payne, vice president of GSK’s antibacterial drug discovery unit, lauded the compound, now renamed GSK2251052, as having “the potential to be the first new-class antibacterial to treat serious hospital gram-negative infections in 30 years.” GSK chemists have since developed a stereospecific synthesis for commercial-scale production.

As for AN2690, Anacor launched Phase III clinical trials in December 2010. The company had licensed the compound to Schering-Plough in 2007, in exchange for a $40 million payment, but Merck & Co. returned commercialization rights in early 2010, some six months after acquiring Schering-Plough.

Despite two solid successes together, today Anacor is using Naeja only for microbiology screening. Anacor has expanded its internal chemistry group, and like many drug companies big and small these days, it has shifted most of its discovery chemistry outsourcing to Asia.

The recession and the shift of outsourcing to companies in India and China have taken their toll on Naeja, Micetich confirms. Employment at the firm has fallen from a peak of 130 to about 75 today.

Micetich is confident, though. “Part of the secret to our success thus far is that the type of chemistry you farm out to these countries is different from what you can do in North America,” he says. “We’re involved in patents. We bring in biology when it’s needed.”

Discouraged by low productivity and miscommunication, customers that outsourced chemistry to China and India are starting to come back, Micetich maintains. “They are saying, ‘Sure, we’re saving money, but we are not getting the same productivity.’ ”

Hernandez has no complaints about his Asian partners. Still, he does look back fondly on Anacor’s chemistry collaboration with Naeja, recalling the quality of its scientists, their excellent communication skills, and the closeness of the interaction between the two firms. “We treated the chemists on the program like they were Anacor chemists,” he says.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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