New drug blocks "undruggable" target in cancer cells
(21 November 2009: VIDYYA MEDICAL NEWS SERVICE) -- Researchers have created a new type of cancer drug that blocks a “master” protein considered to be untouchable by conventional agents. A team from Harvard University used the drug to suppress signals from a growth-promoting pathway, the Notch signaling pathway, that switches on inappropriately in some cancers. Cancer cells that depend on Notch signaling die when the pathway is blocked, Drs. Gregory L. Verdine, James Bradner, and their colleagues reported in the November 12 Nature.
The drug’s primary target is Notch1, a transcription factor that regulates genes involved in the growth and survival of cells. Transcription factors are mutated in various cancers, but these proteins have proved difficult to target directly because of their structures.
To solve this problem, the Harvard team, led in the lab by graduate student Raymond Moellering, designed a drug molecule (called SAHM1) that enters cells and interferes with a protein-protein interaction that is essential for the transmission of cell growth signals via the Notch pathway.
The researchers tested the drug using cells from patients with T-cell acute lymphoblastic leukemia (T-ALL) and a mouse model of the disease. The Notch1 gene is mutated in half of patients with T-ALL and produces an inappropriately active Notch1 protein. Activated Notch signaling has been seen in several other cancers, including lung, ovarian, and pancreatic cancer, and melanoma.
“We’ve drugged a so-called undruggable target,” said Dr. Verdine. “This study validates the notion that you can target a transcription factor by choosing a new class of molecules, namely stapled peptides.” The strategy may work for other transcription factors because the molecular logic of these proteins is similar to that of Notch1, he added.
In an accompanying editorial, Drs. Paramjit Arora and Aseem Ansari said that the group’s “remarkable results highlight the potential of molecules that mimic the secondary structures of proteins to target normally intractable protein-protein interactions.”
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