Truly boronic

cover story: drug platforms Truly boronic By Michael J. Haas, Senior Writer Researchers at Tufts University have shown that peptide boronic acid inhibitors of dipeptidyl peptidase-4 could provide effective, low-toxicity treatments for diabetes.1 The findings challenge the long-held assumption that boronic acids are too toxic for therapeutic use. Arisaph Pharmaceuticals Inc. has already in-licensed the related IP and has ARI-2243, a boronic acid inhibitor of dipeptidyl peptidase-4, in Phase I testing to treat diabetes. Other companies contacted by SciBX said the findings make the case for taking another look at boronic acids as therapeutics, but they noted that the high potency makes selectivity a key issue, because that potency increases the likelihood of off-target effects at therapeutic doses. Boronic acid redux Dipeptidyl peptidase-4 (DPP-4) is expressed in many mammalian cells and tissues and plays a role in glucose metabolism. The serine protease degrades glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP), two gastrointestinal hormones secreted in response to the intake of food and involved in regulating insulin and glucose production. Two non–boronic acid DPP-4 inhibitors are already approved for type 2 diabetes: Januvia sitagliptin, a selective DPP-4 inhibitor from Merck & Co. Inc., and Galvus vildagliptin, a nonselective DPP-4 inhibitor from Novartis AG. Two other non–boronic acid DPP-4 inhibitors are in registration for the indication: Onglyza saxagliptin from partners Bristol-Myers Squibb Co., AstraZeneca plc and Otsuka Pharmaceutical Co. Ltd. and alogliptin from Takeda Pharmaceutical Co. Ltd. However, dipeptide boronic acids were among the first—and are still among the most potent—inhibitors of DPP-4, according to William Bachovchin, leader of the Tufts team and CSO of Arisaph. In 1991, he and colleagues at Tufts reported the discovery of dipeptide boronic acids with binding affinities for DPP-4 that extended into the picomolar range.2 But he said that long-held—though unproven—assumptions about the intrinsic toxicity of boronic acids have largely precluded their commercial development. Indeed, the only marketed boronic acid drug is Velcade bortezomib, a proteasome inhibitor from Millennium Pharmaceuticals Inc. that is approved to treat multiple myeloma (MM) and mantle cell lymphoma. Millennium, a unit of Takeda, markets Velcade in the U.S., whereas Johnson & Johnson markets the drug elsewhere. In a paper in the Journal of Medicinal Chemistry, the Tufts team compared DPP-4 inhibitors to test whether boronic acids were indeed more toxic than other classes of molecules. SciBX: Science–Business eXchange The group chose three dipeptide boronic acid inhibitors of DPP-4: Val-boroPro talabostat, Ala-boroPro and Glu-boroAla. Talabostat and Ala-boroPro were potent but nonselective. The molecules had low picomolar binding affinities for DPP-4 and low nanomolar binding affinities for DPP-8 and DPP-9. Talabostat also inhibits fibroblast activation protein (FAP). The third compound, Glu-boroAla, was more selective, with a low nanomolar binding affinity for DPP-4 but micromolar binding affinities for DPP-8 and DPP-9. Talabostat was being developed by Point Therapeutics Inc., but a Phase III trial was halted last year when the talabostat arm showed lower overall survival than the control arm. Point reverse merged with DARA BioSciences Inc. later that year. All three compounds lowered blood glucose in mice and rats at least as well as two non–boronic acid DPP-4 inhibitors—one selective, the other nonselective—examined in an earlier study at Merck Research Laboratories.3 The Tufts team also found that the maximum tolerated dose for GluboroAla in rats was comparable to the two non–boronic acid DPP-4 inhibitors. The university team concluded that dipeptide boronic acids can be potent inhibitors of DPP-4 and are not intrinsically more toxic than non–boronic acid inhibitors of DPP-4. Bachovchin told SciBX that in his team’s unpublished experiments in animal models, dipeptide boronic acids showed greater efficacy than sitagliptin, as measured by lower levels of glucose and hemoglobin A1c. “It is always encouraging to see science push the conventional boundaries and challenge perceptions of what is achievable,” said Chris Claiborne, senior director of medicinal chemistry at Millennium. Boronic acids do not have any intrinsic limitations as potential therapeutics, and “this publication will enhance interest in the use of boronic acid derivatives to selectively target proteases for therapeutic areas outside oncology,” he said. Dispelling a bad rap Other companies and academics contacted by SciBX agreed that the JMC report is a major step forward in dispelling the misconceptions about boronic acid toxicity. The consensus is that the data could revive therapeutic interest in the class, if off-target activity against other serine proteases can be curbed. Historically, boronic acid has not been considered a likely pharmacophore, due in part to numerous reports in the 1950s and 1960s of infants who died as a result of accidental ingestion of boric acid.4,5 In the 1980s and 1990s, E.I. du Pont de Nemours and Co. held patents on boronic acids as inhibitors of elastase, thrombin and other proteolytic enzymes, but “people assumed that they must be toxic because du Pont didn’t do anything with them,” Bachovchin said. However, Charles Kettner, who co-discovered du Pont’s boronic acid elastase inhibitors in the 1980s, told SciBX that the compounds exhibited no obvious adverse effects in animals or in cell culture. du Pont was not interested in developing the compounds, he said, because the company Copyright © 2008 Nature Publishing Group  cover story did not have the appropriate biological resources at the time. Indeed, boronic acid DPP-4 inhibitor, dutogliptin (formerly PHX1149). Phase III du Pont did not shy away from developing boronic acids when the com- testing is expected to start this year. pany expanded its focus in the late 1980s to include pharmaceuticals. Kettner was a research fellow when he retired from Bristol-Myers Making a comeback Squibb in 2003. Although selectivity is usually essential for drugs, off-target effects are “du Pont was ahead of its time with its work,” said John Kozarich, not always toxic or unwelcome. A case in point is the boronic acid that chairman and president of ActivX Biosciences Arisaph has in the clinic. Inc., a subsidiary of Kyorin Pharmaceutical Co. “ARI-2243’s effect goes beyond DPP-4 inhibi“This publication will Ltd. “It was done before human genome studies tion,” said Bachovchin. “It lowers blood glucose enhance interest in the use revealed how broad the class of serine proteases is even in DPP-4 knockout animals. So, we are of boronic acid derivatives and how many thrombin homologs there are.” looking for the second mechanism that explains to selectively target He estimated that there are 300 serine protethis enhanced eff (...truncated)