Analyzing the genetic mutations linked with diseases such as cancer has yielded many potential drug targets. However, a significant number of these proteins are considered "undruggable," mainly because their structure is too floppy for any kind of small-molecule drug to bind to it.
Angela Koehler, an associate professor of biological engineering at MIT, has made it her mission to find ways to drug these targets. By taking aim at proteins that interact with the undruggable proteins, she can indirectly disable them or reduce their impact. This approach has already yielded one potential cancer drug that is in early-stage clinical trials, with others in the pipeline.
"In our lab, we think about multiple molecular strategies to perturb the function of the transcriptional regulatory network that a target resides in. Sometimes that's directly going after the target, and sometimes that's leveraging partner proteins," says Koehler, who is also a member of MIT's Koch Institute for Integrative Cancer Research.
Koehler, who trained as a chemical biologist, wears many different hats as the leader of her research group. On any given day, she may focus her attention on studying the biology of protein interactions, engineering new tools to analyze these interactions, developing chemical approaches to designing new drugs, or spinning out startups and working with pharmaceutical companies on potential drug compounds.
"The measure of success of MIT is the impact that you make, whether that's writing papers or translating your work to the wider world," she says. "Increasingly we are either spinning assets out of our lab into biotech companies or partnering with pharmaceutical companies. We're trying to lower the barrier for our colleagues in industry to think about some of these more challenging targets."
"Biologically interesting problems"
Koehler, who grew up in Portland, Oregon, was 4 years old when nearby Mount St. Helens erupted in 1980, an event that both terrified her and spurred her interest in science.
"Every year, to help get me over the trauma of living next to a volcano, my parents would take us up to the mountain," Koehler recalls. "Each year, you could go a little further, but at first it was just blanket devastation. Later, you could see fields that were growing with flowers, and the life starting to come back."
Seeing that devastation and recovery up close inspired an interest in geology and later other areas of science, especially biology. At Reed College, she started out pre-med but soon realized she was more interested in the molecular aspects of biology than in becoming a doctor.
During her junior year at Reed, Barbara Imperiali, then a professor of chemistry at Caltech (and now an MIT faculty member), came to give a lecture that Koehler remembers as the event that inspired her to go to graduate school and pursue a career in academia.
"She came to Reed and gave this amazing lecture in an area called bioorganic chemistry. She was applying her skills as a chemist toward biologically interesting problems, and then engineering new types of molecules and tools. And I thought, I want to be just like her when I grow up," Koehler says. "That lecture was one of the solidifying moments for me to realize, oh, I want to go do a PhD."
After spending her first year of graduate school at Caltech, Koehler moved to Harvard University to finish her PhD, working with Stuart Schreiber, a professor of chemistry. There, she started developing technology that her MIT lab uses now, which consists of microarrays of small molecules that can be screened for activity against target proteins.
Around the time that she finished her PhD, Schreiber, MIT Professor Eric Lander, and others were making plans for a research institute that would build on the initial mapping of the human genome. The logical next step was to try to determine the functions and properties of the many newly discovered genes that appeared in the genomic map. Koehler's work developing technology to analyze the properties of proteins seemed like a good fit, so in 2003, she joined the newly founded Broad Institute of MIT and Harvard.
At the Broad, she set up a high-throughput screening center that has yielded insight into the role of proteins linked to specific diseases, and helped to identify drugs that can target them. In 2013, she decided she was ready to switch to a tenure-track position and began applying for faculty jobs, including one in the MIT Department of Biological Engineering. Her research also drew interest from the Koch Institute leadership, and she ended up being hired as an assistant professor in biological engineering, with her lab at the Koch Institute.
Tackling difficult targets
Although she didn't formally study engineering, Koehler's training as a chemical biologist closely parallels the field that at MIT is called biological engineering, she says.
"A chemical biologist uses chemical tools and methods to study biological systems and modulate biological systems, and also makes things, just like biological engineers make things," she says. "Biological engineering was by far the best fit for me given that chemical biologists often like to think quantitatively."
In her lab at MIT, which is populated by chemists, biologists, engineers, and computer scientists, Koehler focuses on finding ways to drug certain undruggable targets. Much of her work centers on a protein called Myc, which is overexpressed in about 70 percent of cancers. Myc is a transcription factor, meaning that it controls the expression of many other genes. Overexpression of Myc leads to uncontrolled cell growth and proliferation.
Like other molecules considered undruggable, Myc is very floppy, like a strand of spaghetti. Without a distinct structure, it is very difficult to find small molecules that will bind to and inhibit it. Instead, Koehler has focused on targeting other proteins that have crucial partnerships with Myc.
So far, her work has generated potential drug candidates that target a protein called Max, which is a necessary partner for Myc, and another that targets a molecule called CDK9, which regulates Myc's activity. The latter compound is now in early-stage clinical trials run by Kronos Bio, a company co-founded by Koehler.
"Going after Myc's neighbor proteins has turned out to be a more tractable strategy," Koehler says. "We're now applying what we've learned to not only other transcription factors, but other undruggable targets like RNA-binding proteins or cytokines, which are undruggable for different reasons."
Spinning her research out into companies that could use it to develop potential therapeutics is a key goal of Koehler's lab. She also co-teaches a course in the science and business of biotechnology, which focuses on developing ways to bring technologies developed in academia into wider use.
"When I was a graduate student at Harvard, I never thought that I would care about that translational piece, but that's part of the lifeblood of the MIT community," Koehler says. "If your technology or your idea has legs, we spend a lot of time here in the MIT community thinking about how to deploy that technology. That's another reason why I feel kinship with engineers, even though I don't have a formal degree in engineering. Engineers are very focused on trying to make sure that their idea or invention is well-poised to be deployed to the wider world and to make an impact."
