The Undruggables

The Undruggables Can young biotechs chasing elusive drug targets succeed where so many have failed? They think so. G-protein coupled receptors in the cell membrane Courtesy of Anchor Therapeutics and Arkitek Studios John Andrews finished his presentation and turned to the roomful of pharmaceutical employees. Chief scientific officer for NeurAxon, a small Canadian biotech developing pain therapeutics, Andrews braced himself for the onslaught. The comments came rapid-fire: Can it be produced efficiently? Yes, in just a few steps. It is really soluble? It has been from day one. Is it truly selective? Yes. Related Articles 1 Courtesy of Anchor Therapeutics and Arkitek Studios There are many undruggable targets with enormous therapeutic and economic potential that have rankled even the best-funded laboratories over the years. Their names—Bcl-2, Ras, beta-catenin, p53, Mcl-1—are enough to induce a glassy-eyed look from scientists and a skeptical grunt from pharma executives and investors.“The word ‘undruggable’ is a profoundly important one because it has a powerful psychological effect,” said Stuart Schreiber, director of the Chemical Biology Program at the Broad Institute in Cambridge, Massachusetts, in a 2009 news article on the Institute’s Web site.2 “It limits what people think can be done,” added Schreiber, a member of The Scientist’s editorial advisory board.At least, it used to. Today, companies like NeurAxon are capitalizing on the decades of research on these slippery targets and demonstrating some the first successes in reaching them. NeurAxon already has two nNOS inhibitors in clinical trials, one for neuropathic pain in Phase I and a second for acute migraines already in Phase II. But even with strong data, such previously undruggable targets are never an easy sell, say biotech executives. Even if the new approach targets a well-known molecule and could be worth billions if it works, investors still worry: When pharmaceutical companies have given up on it, maybe it’s not possible.“[Going after undruggable targets] is a risk we take,” says Rick Jones, CEO of Anchor Therapeutics, a biotech in Cambridge, Massachusetts. “People have been banging on it for so long that they have gotten tired of it or just assume it can’t be done.” Two previously undruggable targets: nNos (top) bound to an inhibitor (in red) and Mcl-1 (bottom) modified by a stapled peptide (blue with a red staple) top: Courtesy of NeurAxon Bottom: Courtesy of Aileron But the risks have their rewards. More and more, large pharmaceutical companies are putting their money into innovative, even seemingly crazy, efforts to hit elusive targets. Anchor, for example, is working on drugging a class of supposedly undruggable membrane receptors for Novartis and Ortho-McNeil-Janssen Pharmaceuticals who have paid fees and milestone payments in excess of $200 million and $400 million, respectively. And this past August, Roche committed $25 million up front and another $1.1 billion in milestone payments to Aileron Therapeutics to go after protein–protein interactions, some of the most intractable drug targets in the business. “It’s one of the largest preclinical deals ever done,” says Juan Enriquez, managing director of Excel Venture Management, an investor in Aileron. “You don’t make bets on this scale unless you think there’s something absolutely fundamental and transformative here.” The days of Lipitor—the fifth drug of its type to the market—are over, says Steve Tregay, CEO of FORMA Therapeutics in Cambridge, Massachusetts. Incremental advances against previously drugged targets are simply no longer going to be rewarded in the marketplace. “The premium placed on innovation, new targets, and being first in class is very apparent,” says Tregay. “There really is no low-hanging fruit anymore.”Turning pharma headsAt potential investor meetings, Tregay often witnesses what he calls “sit-up-in-their-seats” moments. He points to a list of high-value targets in oncology, FORMA’s specialty. Perusing the list, investors and pharmaceutical executives lean back in their chairs, remarking on how great it would be to drug any one of those. “Then I say, ‘Let me tell you about where we are on all of them,’” chuckles Tregay. “It really captures their attention.”The premium placed on innovation, new targets, and being first in class is very apparent. There really is no low-hanging fruit anymore.—Steve Tregay, CEO, FORMA TherapeuticsFounded only 2 years ago, the 85-person company already has a partnership with the Leukemia & Lymphoma Society to develop compounds targeting Bcl-6, a transcription repressor that downregulates genes in non-Hodgkin’s lymphoma. Bcl-6 is a member of one of the largest class of undruggable targets—those that exert a function through protein–protein interactions. The proteins c-Myc and K-Ras, for example, are each activated in nearly half of all human cancers, but neither has been successfully targeted with an approved therapy because they function through associations with other proteins, which to date have proven too chemically complicated to affect.But FORMA relishes the challenge. To go after Bcl-6, among other targets, the company employs a unique assay to screen full-length proteins within living cells, then uses computational mapping tools to visualize protein interactions and probe them for novel druggable hotspots. To reduce the risk of going after a single high-value target, FORMA tackles many at the same time. “We’ll run close to 15 different highly validated ‘holy grail’ oncology targets this year alone,” says Tregay. “Yes, these are incredibly hard targets, and, no, we won’t succeed against all of them. But that’s why we’ve built an infrastructure to dwarf a traditional biotech’s productivity.”Anchor Therapeutics, a Tufts Medical Center spin-off that opened its laboratory doors in 2008, has its sights set on a different, yet tempting, family of undruggables—G-protein coupled receptors (GPCRs). Despite the facts that these membrane receptors are involved in almost all signaling pathways in the human body and that nearly one-third of commercialized drugs target GPCRs, only about 10 percent have been drugged.3 Anchor’s approach to GPCRs is literally inside out: They have demonstrated an ability to activate or inhibit GPCRs from inside cells by using pepducins, peptides with short lipid tails that anchor in a cell membrane. Once the pepducin is latched on to the membrane, it flips into the intracellular space to hit the interior portion of a GPCR, altering the receptor’s shape to increase or inhibit activity. “We can go after any kind of GPCR,” says Jones, CEO of the company, including orphan GPCRs with no known natural ligand. “Other people, in the absence of a natural ligand, can’t even begin to work with those receptors.”Anchor’s drug candidates include an agonist pepducin for CXCR4, a GPCR found on progenitor cells of the immune system that directs them to areas of injury. Many companies have designed antagonists of CXCR4, including Genzyme’s Mozobil, which prevents blood stem cells from localizing in the bone marrow so that they are released into the circulation instead, where they can be harvested for stem cell transplants. But an agonist for CXCR4 has proven more difficult to manufacture. Anchor’s candidate would be the first to market.In contrast to CXCR4 antagonists, the new drug increases the cells’ ability to hone in on areas of injury, such as a bone fracture or heart tissue damaged by a heart attack. The company is also pursuing GPR39, an orphan receptor for the treatment of Type 2 diabetes, and C5A, a protein fragment that binds a GPCR implicated in inflammatory conditions. “We’ve chosen to concentrate on targets that we believe have been difficult for other people to hit,” says Jones, “so it will likely result in a first-in-class molecule.”One of the most talked-about biotechs going after undruggables is Aileron Therapeutics of Cambridge, Massachusetts. Last year, the company secured $40 million from a quartet of big pharma companies—Novartis, Roche, Eli Lilly, and GlaxoSmithKline—to develop their stapled peptide platform, a technology that stabilizes synthetic peptides with a chemical “staple” so they don’t lose their shape, like a slinky held together with a twist-tie. While most peptides are digested by enzymes in the bloodstream within minutes of injection, stapled peptides, which can target protein–protein interactions, hold their shape for up to several days.“When you get four pharmas into the same deal, and there aren’t guaranteed targets, that’s telling you that they’re not looking at this for a blockbuster compound, but as a new industry,” says investor Enriquez, who co-led the $40 million round of financing for the company. And with the additional billion-dollar commitment from Roche last August, Aileron plans to start clinical trials next year. Someday soon, “undruggables” could be nothing but a misnomer if these biotechs fulfill their lofty goals. But above all, the pharmaceutical industry should not give up on difficult drug targets, says Andrews. “Our job is not to produce the same old stuff, ” he says. “Our job is to make things [that] improve people’s lives…and these high-hanging fruit are some of the best ways to do that.”References: 1. G.L. Verdine, L.D. Walensky. “The challenge of drugging undruggable targets in cancer: Lessons learned from targeting BCL-2 family members,” Clin Cancer Res, 13:7264-70, 2007. 2. N. Davis, “The next frontier of modern science: the “undruggable,” Broad Institute, 11 Nov 2009, available online at http://www.broadinstitute.org/news/1380 3. D.K. Vassilatis et al., “The G protein-coupled receptor repertoires of human and mouse,” PNAS, 100:4903-8, 2003.

The Undruggables

The Undruggables

Can young biotechs chasing elusive drug targets succeed where so many have failed? They think so.

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