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FROM PEPTIDES TO SMALL MOLECULES Adherex draws on Scynexis' chemistry skills to develop a follow-on to its lead drug candidate
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million Canadian, but its unconventional nature discouraged subsequent investment by professionals. By 2002, Adherex was struggling and in need of firm guidance from experienced managers. That January, the company hired Robin J. Norris, a British-educated medical doctor and veteran of several other biotechfirms,big and small, as chief operating officer. "I rec ognized immediately that it needed strategic help," Norris now says. "A company may have great technology that's going to make fabu lous therapeutics, but to get there you often need to do a lot of business things." He and other managers searched for a "transforming event" to revive Adherex and found it later that year in the form of a merger with Oxiquant, a U.S.-based com pany withrightsto chemoenhancement and chemoprotection technology developed, respectively, by Rutgers University and Or egon Health & Science University. William P. Peters, a veteran oncologist and adviser to Oxiquant, joined Adherex as chief executive officer in March 2003, and he and Norris soon hit the road to tell the new Adherex story to institutional investors. The company was essentially broke when they started the effort, Norris says, but by June 2004 it had more than $20 million in the bank. Today, Adherex employs 30 people at a new headquar ters in Research Triangle Park, N.C., and has com pleted a Phase I clinical trial of ADH-1, an intravenously administered cyclic peptide based on Blaschuk's original EXPERIENCED More than half of the scientists technology. A European pep on Scynexis' staff have Ph.D.s. Two of them are tide specialist manufactures Weiming Fan (left) and Allan Long. the drug's active ingredient, university and angel investors. In 1999, it Norris notes, and another contract produc moved from Montreal to Ottawa. Then, in tionfirmcreates the finished dosage form. 2001, it launched an unusual "retail" initial Phase I and II trials are ongoing in public offering, in which the majority of Europe, the U.S., and Canada, involving stock buyers were average citizens rather patients with tumors that express N-cad than professional investors. herin, a cancer category that can include The offering was successful, raising $10 breast, lung, colon, ovarian, and melanoma,
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DHEREX TECHNOLOGIES HAS
evolved over the past decade from a small Canadian start-up into an established biopharmaceutical firm that has a peptide drug in Phase II clinical trials and a collaboration with one of the drug industry's largest players. Now, with the help of Scynexis, a chemistryfbcused drug discovery and development firm, Adherex is expanding its core technology into the small-molecule realm. Adherex was launched in 1996 as a spinoffirom the McGill University labs of cell bi ologist Orest Blaschuk, who discovered pep tides that inhibit the action of N-cadherin, a protein that straddles the cell wall of certain tumor cells and aids in cell communication. Subsequent cell culture studies found that inhibiting N-cadherin binding between tu mor cells causes apoptosis, or cell death, and tumor vascular disruption by interfering with survival signaling mechanisms. In its early years, Adherex received typ ical start-up company support from the
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Aminosugar Syntons for Oligosaccharides raised $40 million, with afinal$29 million secured in 2002. Later that year, it signed chemistry-based drug research deals with two big pharma firms, Merck & Co. and Roche. Today, Scynexis employs 113 people; 85 are chemists and more than half of those have Ph.D.s. Peel explains that Scynexis started out primarily as a compound-library developer but evolved in itsfirsttwo years to offer drug hit identification, lead optimization, and current Good Manufacturing Practices syn thesis of compounds for Phase I and II clinical tri als. In order to better serve chemistry-poor biotechs, Scynexis spent 2003-04 acquiring skills in related areas such as biometabolism and pharmacokinetic support. Now, Peel claims, "we can take the chemistry side of drug discovery all the way from the crystal structure of a target to lead optimization, then to the iterative process of improving potency and oral bioavailability, and on through toxi cology studies. Adherex is the ideal opportu nity to bring in all of these capabilities." Although Scynexis can start with a drug target and evolve hits from there, in this case it had the benefit of the leads Adherex had identified a fewyears earlier. With 3-D THOSE EARLY EFFORTS yielded several structures of these small molecules in hand, molecules that appeared to block N-cad Scynexis scientists proceeded on two fronts herin binding with even greater potency under the project leadership of medicinal than ADH-1. Because it lacked in-house chemist Gilles Ouvry. chemistry capabilities, Adherex wasn't able On one front, they combined Adherex's to pursue the leads further. But last March, insights into N-cadherin's crystal structure with its financial footing more secure, Ad with their own computational chemistry herex signed an agreement with Scynexis capabilities to screen virtual compound li that allowed it to tackle small-molecule braries in silico. On the other, they worked N-cadherin antagonists in earnest. with other Adherex outsourcing partners According to Norris, Scynexis was one to screen actual small molecules against of several potential chemistry partners that specialized assays. were vetted. Adherex executives were famil One year later, with the help of more iar with the company because of its good than a dozen Scynexis scientists, Adherex local reputation—both firms are based in has several promising small-molecule drug Research Triangle Park—and because Brian candidates in hand. Scynexis medicinal E. Huber, Adherex's chief scientific officer, chemists are now tweaking them to opti knew Michael Peel, Scynexis' director of mize traits like potency, toxicity, and oral medicinal chemistry, from previous stints bioavailability. at GSK. More important, the executives In a perfect world, Norris would let were sold on Scynexis' ability to handle all the chemists tinker until they arrived at the chemistry needs of a small firm's drug the perfect small-molecule antagonist of discovery and development program. N-cadherin. But Adherex operates in the Peel says this full-service ability is rela real world of time-crunched biotech drug tively new for Scynexis. The company was development, and, Norris says, it has a formed in 2000 by a group of former Aven very real target: "Our goal is to get a small us scientists who pooled their severance molecule into clinical trials in 2007."— pay to form a contract chemistry firm. It MICHAEL MCCOY
among others. "In our Phase I experience, we have seen anticancer activity even in single doses," Norris says. "Some patients who received repeated doses had repression of tumor biomarkers or stable disease that persistedforsix or seven months." Adherex hopes to have complete results from some of the trials in the second half of 2006 and to enter Phase III as early as 2007. ADH-1 won a vote of confidence lastJuly when Adherex entered a development and license agreement with GlaxoSmithKline, in which the drug giant made a $3 million equity investment in Adherex. Under the deal, Adherex in-licensed the oncol ogy treatment eniluracil, which had been sitting on the shelf at GSK, while GSK obtained an option to license ADH-1. Although Adherex executives are happy with ADH-l's progress, Norris says they have long seen the potential to develop orally active N-cadherin antagonist thera pies based on small molecules. Such drugs could treat other ailments or become followons to ADH-1. "Even when we were near broke in 2002-03, we did some screening against in-house assays, looking for small molecules," he says.
Syntheses Fine & Specialty Chemicals
OMP
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NPhth 4-Methoxyphenyl 3-OBenzyl4,6-Obenzylidene-2-deoxy2-phthalimido-p-D-glucopyranoside CAS# 129575-88-8 [Ml 609]
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GAGs Glycolipids Glycopeptides
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4-Methoxyphenyl 2-Azido4,6-0-benzylidene-2-deoxyβ-D-glucopyranosiae [Ml 637]
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