Aileron’s New Class of Drugs Shown to Get Inside Cells to Block Prime Cancer Target

11/11/09Follow @xconomy

Cambridge, MA-based Aileron Therapeutics has bet the company on the idea that it has discovered a whole new class of drugs that, like RNA interference, can hit targets in the body that are beyond the reach of conventional chemical compounds and biotech therapies. Today, scientists are reporting the drugs can achieve this goal and block one of the prized targets that has eluded cancer researchers for years.

Scientists at Harvard University, the Dana-Farber Cancer Institute, and the Broad Institute of Harvard and MIT say they have used a synthetic “stapled peptide” from Aileron to get inside the nucleus of cells and stop the production of a protein called Notch that’s implicated in uncontrolled growth of cancer cells, according to research being published this week in Nature. The work was repeated in multiple disease models and in animal tests, which showed blocking this target led to cancer cell death, without the side effects of previous drugs, the researchers said.

This finding is bound to stir curiosity in the cancer research world for Aileron’s stapled peptide drugs. Buzz for the new drug technique picked up in June when Aileron raised $40 million in venture capital from a syndicate that included four major drugmakers—Roche, Novartis, Eli Lilly, and GlaxoSmithKline. While a few other peptide treatments are on the market for diabetes and osteoporosis, most of these drugs don’t work because they get chewed up by enzymes in the body before they can hit their target. Aileron’s key insight is to chemically “staple” these peptides in a way that holds them together in a properly folded shape, protecting them and preserving the unique structure that gives them the ability to hit very specific protein targets inside cells, like Notch.

“There have been many valiant efforts that have gone after this target, and they’ve all failed,” says Aileron CEO Joe Yanchik. “This is the first potentially viable therapy.”

As Yanchik explained to me in a profile of Aileron a year ago, traditional small-molecule chemical drugs, like Pfizer’s atorvastatin (Lipitor), usually need “a nice deep pocket” on the targeted protein for the compound to settle into. The problem is that only about one-tenth of proteins have this kind of pocket, while many more have long, flatter pockets inside that are “like a hot dog bun, for lack of a better term,” he said. Engineered peptides, which are protein fragments, are thought to have improved properties because they are larger than traditional small molecules and able to nestle into some of those bigger pockets, but they aren’t so big they can’t get inside cells, like traditional antibody drugs that operate on the cell surface, Yanchik says. Done right, a stapled peptide ought to be efficient at penetrating cells, and bind tightly enough and long enough to its target to have the intended effect.

Researchers led by James Bradner at Dana-Farber and the Broad Institute as well as Gregory Verdine at Harvard, said they found that the Aileron drug was able to bind directly and tightly to Notch in the nucleus of cells. That target is known as a transcription factor—a protein that binds to DNA in the nucleus of cells and regulate important biological processes. By blocking Notch, the scientists found they could prevent a cancer-causing gene from assembling the necessary proteins to grow, and suppress the production of other growth proteins that cancer cells need to live.

This idea of blocking transcription factors is important because they have been traditionally inaccessible, and there are an estimated 1,500 of these proteins involved in regulating key biological processes involved in diseases such as arthritis, asthma, diabetes, infectious diseases, and cancer, Aileron says.

“These results are tantamount to a declaration of open season on transcription factors,” said Verdine, a professor of chemistry at Harvard University and co-chair of Aileron’s scientific advisory board, in a statement.

Getting inside cells to specifically target previously “undruggable” targets sounds a lot like what gets so many scientists are excited about RNA interference and microRNA technology—which are much better known in the scientific community than stapled peptides.

Yanchik welcomes the comparison.

“One of the big differences is that we can modulate things up or down, on or off,” Yanchik says. “Most drugs are good at stomping on things you want to stop. We can do that, or we can also stimulate an activity that you want.”

Aileron still has a very long road ahead to prove this concept will actually work for new FDA-approved drugs. The company hasn’t yet entered its first clinical trial, and it could take another year to file its first application with the FDA to start a human trial, Yanchik says.

The company currently has 26 employees and is looking to grow by hiring biologists, chemists, and people with drug development experience, Yanchik says. One important recent hire was Diane Jorkasky as chief medical officer: she was previously the worldwide head of clinical research operations for Pfizer (NYSE: PFE), the world’s largest drug company.

Part of Jorkasky’s job will be to evaluate the prospects of Aileron’s drug candidates for clinical trials. But Yanchik wanted to emphasize that Aileron isn’t going to get pigeonholed into becoming a one-product company, as is often the case in biotech companies. Developing a drug does take a lot of focus on a product, and all companies have to set their priorities, but for now he’s still emphasizing the vast potential of stapled peptides as a “platform” technology that can give rise to a whole new class of therapies.

“This paper isn’t just about Notch, it will cause people to think more about the breadth of opportunities,” Yanchik says. “This isn’t about one single drug.”

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