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Angela Koehler: The Small Molecule World

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Recommended by: Stuart Schreiber, Broad Institute

As an undergraduate at Reed College, Angela Koehler majored in biology, thinking she'd become a doctor. But as she put in hours at nearby Oregon Health Sciences University in a crystallography lab, she realized that her true passion was in research, not clinical practice.

"The part of biology I really liked was molecular recognition," she says. "I started to think more about the timing of transcriptional regulation and quickly learned that small molecules could be useful tools for teasing out the temporal aspects of transcriptional regulation. That inspired me to move into the world of chemistry to learn more about small molecules."

As an investigator at the Broad Institute, Koehler now uses high-throughput assays to discover small-molecule probes of transcriptional regulators, such as chromatin-modifying enzymes and oncogenic transcription factors, with the hope that some can be developed for diagnostic or therapeutic applications. Of particular interest to her group is the development of probes for oncogenic transcription factors including Myc, Max, NF-kappaB, and Pax5.

Despite advances made in the field since she began working at the Broad, Koehler notes that there is much work to be done.

"Working with intrinsically disordered proteins like transcription factors is in its infancy in that we still need to figure out basic biochemical methods for producing these proteins and for keeping them from proteolytically degrading," she says. "There are a lot of nitty-gritty technical challenges that a number of groups are trying to address right now.

"Just getting access to the proteins can be a challenge," Koehler adds.

Paper of note

In one effort, she collaborated with the Broad's Stuart Schreiber and researchers from Massachusetts General Hospital to screen small molecules that bind to the extracellular protein Sonic hedgehog and block its signaling. "We identified a subset of hits, then worked with his group to refine them and optimize them and understand a little bit more about the mechanism of action," Koehler says.

"I like that one because it allowed us to work with … a number of labs inside the Broad,as well as outside the Broad," she added. "I like sitting in a room where you have a combination of physicians, scientists, chemists, biologists, computational scientists all trying to wrap their heads around a single problem."

And the Nobel goes to...

If she were to win a Nobel Prize, Koehler would like to do so for making strides in expanding the druggable genome and clarifying the therapeutic potential of master regulators in cancer.

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