Stabilized Helix Cracks Cancer Target

With the help of a helix-stabilizing strategy, researchers have developed the first direct inhibitor of the Notch transcription factor complex, which is implicated in a range of cancers. The work may inspire a new class of cancer drugs.

Transcription factor proteins are master cell regulators with potential as cancer drug targets. However, with the exception of transcription factors such as the estrogen receptor, which have hydrophobic pockets for binding small molecules, it’s been hard to find agents that alter their activity.

Now, chemical biologists Gregory L. Verdine of Harvard University and James E. Bradner of Dana-Farber Cancer Institute, their graduate student Raymond E. Moellering, and colleagues have capitalized on structural insights to develop an α-helical blocker of Notch, which is out of whack in over 50% of patients with a specific type of leukemia (Nature 2009, 462, 182).

“One of the many difficulties with identifying direct inhibitors of transcriptional complexes is that that there is often little structural information about them,” says Anna Mapp, who develops artificial transcription factors at the University of Michigan, Ann Arbor. The Boston team benefited from previous work by coauthor Stephen C. Blacklow of Brigham & Women’s Hospital and others, who showed how the three-component Notch complex assembles before binding to DNA. They noticed a protein-protein interaction in the complex that required a key α-helix. They decided to generate a stabilized helix to disrupt that interaction and shut down Notch.

At that point, the team turned to peptide stapling, a technique Verdine perfected that locks helical peptides into place via olefin metathesis (C&EN, June 2, 2008, page 18). Experiments in cultured cells and mice showed that one stapled peptide, called SAHM1, efficiently enters cells and selectively limits the growth of cancers 
fueled by Notch defects.

“For the bulk of cancer-related transcription factors there are no therapeutic agents and few, if any, chemical tools,” Bradner says. But because other transcription factors assemble in this way, the stapled-peptide approach might be a general strategy for manipulating them.

“With this approach, we are declaring open season on transcription factors,” Verdine says. Verdine is the scientific founder of Aileron Therapeutics, a company developing stapled-peptide drugs. Aileron is currently negotiating a license to the patent on SAHM1, Verdine tells C&EN.

This work provides more evidence that blocking Notch might work against cancer and showcases the power of stabilized helices for tackling tough targets, says David Cowburn of the New York Structural Biology Center, who has also worked with stapled peptides. “It is important to evaluate whether this kind of compound can be clinically effective in humans,” he says.