Scientists have devised an
innovative way to disarm a key protein considered to be “undruggable,” meaning
that all previous efforts to develop a drug against it have failed. Their discovery,
published in today’s edition of the journal Nature, lays the foundation for a new therapy
aimed directly at a critical human protein — one of a few thousand so-called
transcription factors — that could someday be used to treat diseases, especially
multiple types of cancer.
“There is a pressing need for
drugs that target transcription factors, both for use as scientific tools in
the laboratory and as therapies in the clinic,” said senior author James
Bradner, a Harvard Medical School chemical biologist and oncologist at the Dana-Farber Cancer
Institute and an associate member of the Broad Institute of Harvard and MIT.
“Our work brings us a step closer toward that goal for a protein with major
roles in cancer, cardiovascular disease, and stem cell biology.”
If human physiology is like a
puppet show, then transcription factors pull the puppet strings. They bind to
DNA and turn genes on or off, setting in motion genetic cascades that control
how normal cells grow and develop. They also help maintain tumor growth,
underscoring their importance as cancer drug targets. Yet transcription factors
are counted among the most difficult molecules to neutralize with a drug. In
fact, no such drugs are currently available.
Based on his oncology work, Bradner
became deeply interested in a human protein called NOTCH. The gene encoding
this protein is often damaged, or mutated, in patients with a form of blood
cancer known as T-ALL, or T-cell acute lymphoblastic leukemia.
Abnormal NOTCH genes found in
cancer patients remain in a state of constant activity, switched on all the
time, which helps to drive the uncontrolled cell growth that fuels tumors.
Similar abnormalities in NOTCH also underlie a variety of other cancers,
including lung, ovarian, pancreatic, and gastrointestinal cancers.
Even with this deep scientific
knowledge, drugs targeting NOTCH — or any other transcription factor — have
traditionally been extremely difficult, if not impossible, to develop. Most
current drugs take the form of small chemicals (known as “small molecules”) or
larger-sized proteins, both of which have proven impractical so far for
disabling transcription factors.
A few years ago, Bradner and his
colleagues hatched a different idea about how to tame the runaway NOTCH
protein. Looking closely at its structure as well as the structures of its
partner proteins, they noticed a key protein-to-protein junction that featured
a helical shape.
“We figured if we could generate a
set of tiny little helices, we might be able to find one that would hit the
sweet spot and shut down NOTCH function,” said Bradner.
Creating and testing these helices
involved a team of interdisciplinary researchers, including Greg Verdine,
Erving Professor of Chemistry in Harvard’s Department of Chemistry and Chemical Biology, and director of the
Chemical Biology Initiative at Dana-Farber Cancer Institute, as well as
scientists at Brigham and Women’s Hospital and the Broad Institute’s Chemical
Biology Program, which is directed by Stuart Schreiber, Morris Loeb Professor
Verdine invented a drug-discovery
technology that uses chemical braces, or “staples,” to hold the shapes of
different protein snippets. Without these braces, the snippets (called peptides)
would flop around, losing their three-dimensional structure and thus their
Importantly, cells can readily
absorb stapled peptides, which are significantly smaller than proteins. That
means the peptides can get to the right locations inside cells to alter gene
“Stapled peptides promise to
significantly expand the range of what’s considered ‘druggable,’ ” said
Verdine, who is a co-senior author of the study and an associate member of the
Broad Institute. “With our discovery, we’ve declared open season on
transcription factors and other intractable drug targets.”
After designing and testing
several synthetic stapled peptides, the research team identified one with
remarkable activity. Not only could it bind to the right proteins and reach the
right places inside cells, it also showed the desired biological effect: the
ability to disrupt NOTCH function.
Moreover, experiments in cultured
cells as well as in mice proved the peptide’s ability to limit the growth of
cancer cells fueled exclusively by NOTCH. Interestingly, these effects are also
seen at the level of gene activity, or “expression.” The researchers looked at
the expression levels of genes across the genome, in both cells and mice
treated with the peptide, and observed markedly reduced expression of genes
that are controlled directly and indirectly by NOTCH. These results offer some early
insights into how the peptide works at a molecular level.
In addition to its potential
therapeutic applications to NOTCH-dependent cancers, the Nature study discovery
also forms the basis of a general strategy for taking aim at other
transcription factors. “A variety of key transcription factors assemble in a
manner similar to NOTCH,” said first author Raymond Moellering, a graduate
student in the Harvard Department of Chemistry and Chemical Biology
who works with Verdine and Bradner. “Our approach could offer a template for
targeting many other master regulators in cancer.”
Funding for the research was provided by the
Leukemia and Lymphoma Society, the American Association for Cancer
Research, the American Society of Hematology, the Harvard/Dana-Farber
Program in Cancer Chemical Biology, the National Institutes of Health, and
other funding organizations.