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Direct inhibition of the NOTCH transcription factor complex
NATURE, Vol 462, 12 November 2009, 181-188.
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The Notch signaling pathway, Nature Reviews Cancer 6, 347-359 (May 2006)
what do we have here:
This group has developed a new drug that blocks Notch (and therefore its signaling) -- previously thought to be un-blockable -- that has been causally linked to leukemia and several other cancers of the lungs, ovaries, pancreas, and the gastrointestinal tract.
The problem to find a suitable drug, I guess, was the rather large number of proteins in the Notch-activating-complex, and this group has ultimately targeted the master-mind protein MAML which must bind to the complex along a long, shallow helical groove, which is created as the other pieces come together.
They developed a way to essentially "staple" a synthetic peptide into a complementary helical shape, allowing it to fit into the groove.
The researchers tested the stapled peptides on human T-cell acute lymphoblastic leukemia (T-ALL) cell lines. Additionally, mice injected with T-ALL cells and treated with the stapled peptides showed lower leukemia counts in the bone marrow and spleen than those that went untreated.
Insights / Hopes/ Doubts:
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This paper at least, dispels despair among oncologists and organic-chemists about peptides acting as leads for drug discovery and well, hopefully this becomes a commercially viable treatment-option!
But then, obviously, blocking an omni-present signaling-system could have other side-effects.
And whether this peptide-based approach could be extended to other treatments as well, remains to be seen.
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