In initial studies of mice injected with luciferase-expressing leukemia cells, median survival for those injected for seven days with 10mg/kg of Aileron’s first lead stapled peptide was 11 days, up from five days for untreated controls. A significant decrease in tumor growth was also observed. “The half-life for the lead stapled peptide after intravenous injection was observed to be 1.6 hours, unusually long for a peptide. We’re very happy with that,” Dr. Nash says. He adds that clinical trials are planned for the end of 2008 or early 2009.
Proteolix (www.proteolix.com), on the other hand, is already in the clinic. It took its lead compound from discovery to Phase I trials within a year, according to a presentation to be made at Cambridge Healthtech’s “TIDES” conference next week in Las Vegas. Carfilzomib, a peptide-based proteasome inhibitor, is being developed to treat hematological cancers.
Chris Molineaux, Ph.D., vp, development, compares the compound to bortezomib (Millennium Pharmaceuticals’ Velcad®), noting some important differences. While both are peptides, carfilzomib has four amino acids with an epoxyketone warhead, versus Velcade’s two amino acids and boronate warhead. “Carfilzomib may bind differently to the proteasome,” Dr. Molineaux says. “With carfilzomib, the peptide, not the epoxyketone warhead, drives the binding to the target enzyme. For bortezomib, the warhead itself is critical.”
In preclinical studies, Proteolix’ compound appears to be a more specific proteasome inhibitor. In looking at a panel of enzymes that may reflect off-target activity, “bortezomib has been shown to inhibit several serine proteases with micromolar or submicromolar activity, while carfilzomib, at a higher concentration, inhibits only a few.” Early preclinical studies, he says, indicated that carfilzomib was better tolerated and could be administered daily to provide extensive proteasome inhibition.
The development premise was that carfilzomib would be efficacious at its maximum tolerated dose. Early dose-progression studies bore that out, according to Proteolix. “At the maximum tolerated dose, we are getting substantial inhibition of the target enzyme—up to 85%,” Dr. Molineaux reports. Consequently, more intensive dosing appears possible; up to daily doses for five consecutive days.
Carfilzomib also appears less toxic than bortezomib, he adds, noting that of “more than 50 patients treated, some for more than one year, none have developed naturopathic pain.” The reason for lower toxicity remains speculative but “may be related to off-target inhibition of some other enzyme by bortezomib.” Dr. Molineaux believes that this compound may have applications in solid tissue tumors.
Currently, the company is scaling up production and completing the FDA approval process. “We worked with manufacturers early in development, using the most straightforward manufacturing process we could put together,” Dr. Molineaux states. Although he knew it would have to change to accommodate large-scale manufacturing processes, the goal was to initiate clinical development to get proof of concept for carfilzomib as soon as possible.
Genentech’s (www.gene.com) approach to anticancer treatments uses a peptide to inhibit cyclinA, according to Daniel Sutherlin, Ph.D., scientist, medicinal chemistry. Dr. Sutherlin, speaking at the “Protein-Protein Interactions as Drug Targets” conference explained that cyclinA is integral in the cell cycle and is considered an important cancer target.
Unlike most small molecule drug discovery programs, Genentech is focusing on “inhibitors that bind to a substrate recognition groove on the surface of cyclin A,” Dr. Sutherlin says. “Peptides that mimic endogenous substrates and inhibitors of the kinase complex bind to this site,” and using peptides to inhibit cyclinA is selectively killing cancer cells both in vitro and in vivo, he explains. Genentech currently is validating this site as a small molecule target.
7TM Pharma (www.7tm.com) is in Phase I and II trials for obesity therapies. TM30339 works through the Y4 receptor and is in Phase I/II development. TM30338 targets the Y2 and Y4 receptors and is being evaluated in Phase II. Considered first-in-class compounds, they have a mechanism of action similar to that of the natural satiety hormone pancreatic polypeptide and mimic natural satiety, thus helping regulate food intake, explains Paul Little, Ph.D., senior chemist. Dr. Little will be presenting this research at “TIDES”.
As its name implies, the company focuses on seven transmembrane receptors. Rather than launching a high-throughput screening campaign, 7TM has developed its Site Directed Drug Discovery® platform to provide targeted libraries.