Analysis of genetic mutations linked to diseases such as cancer has yielded many potential drug targets. However, a significant number of these proteins are considered “non-druggable”, mainly because their structure is too flexible for any type of small molecule drug to bind to them.
Angela Koehler, an associate professor of biological engineering at MIT, has made it her mission to find ways to drug these targets. By targeting proteins that interact with non-drug proteins, it can indirectly disable them or reduce their impact. This approach has already yielded a potential cancer drug that is in early-stage clinical trials, with others in the pipeline.
“In our lab, we think of multiple molecular strategies to disrupt the function of the transcriptional regulatory network in which a target resides. Sometimes this goes directly after the target, and sometimes it takes advantage of partner proteins,” says Koehler , who is also a member. from 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, you can focus your attention on studying the biology of protein interactions, designing new tools to analyze these interactions, developing chemical approaches to designing new drugs, or starting new companies and working with pharmaceutical companies on potential pharmaceutical compounds.
“The measure of success at MIT is the impact you have, whether it’s writing papers or translating your work to the wider world,” he says. “Increasingly we’re turning our lab assets into biotech companies or partnering with pharmaceutical companies. We’re trying to lower the barrier for our industry colleagues to think about some of these more difficult targets.”
“Biologically interesting problems”
Koehler, who grew up in Portland, Ore., was 4 years old when nearby Mt. St. Helens exploded in 1980, an event that terrified her and spurred her interest in science.
“Every year, to help me get over the trauma of living next to a volcano, my parents would take us to the mountains,” Koehler recalls. “Every year, you could go a little further, but at first it was just widespread devastation. Later, you could see fields growing with flowers and life was starting to come back.”
Seeing that devastation and recovery up close inspired an interest in geology and later in other areas of science, especially biology. At Reed College, she began pre-med, but soon realized she was more interested in the molecular aspects of biology than in becoming a doctor.
During her first year at Reed, Barbara Imperiali, then a professor of chemistry at Caltech (and now a faculty member at MIT), came to give a lecture that Koehler remembers as the event that inspired her to go to the school graduate 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 to biologically interesting problems, and then designing new kinds of molecules and tools. And I thought, ‘I want to be like her when be big,” says Koehler. “This conference was one of the solidifying moments because I realized, oh, I want to go and do a Ph.D.”
After spending his first graduate year at Caltech, Koehler transferred to Harvard University to finish his doctorate, working with Stuart Schreiber, professor of chemistry. There, he began developing the technology his MIT lab now uses, which consists of microarrays of small molecules that can be screened for activity against target proteins.
By the time he finished his 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 next logical step was to try to determine the functions and properties of the many recently discovered genes that appeared on the genomic map. Koehler’s work developing technology to analyze the properties of proteins seemed like a good fit, so in 2003 he joined the newly founded Broad Institute at MIT and Harvard.
At the Broad, he created a high-throughput screening center that has provided insight into the role of proteins related to specific diseases and helped identify drugs that can target them. In 2013, she decided she was ready to transition to a tenure-track position and began applying for faculty jobs, including one in MIT’s Department of Biological Engineering. Her research also attracted the interest of the leadership of the Koch Institute, and she ended up being hired as an assistant professor of biological engineering, with her laboratory at the Koch Institute.
Tackling difficult goals
Although she didn’t formally study engineering, Koehler’s background as a chemical biologist closely parallels the field at MIT called biological engineering, she says.
“A chemical biologist uses chemical tools and methods to study biological systems and modulate biological systems, and he also makes things, just like biological engineers make things,” he says. “Biological engineering was by far the best choice for me, as chemical biologists often like to think quantitatively.”
In his MIT lab, which is populated by chemists, biologists, engineers and computer scientists, Koehler focuses on finding ways to drug certain non-druggable targets. Much of their work focuses on a protein called Myc, which is overexpressed in about 70 percent of cancers. Myc is a transcription factor, meaning it controls the expression of many other genes. Overexpression of Myc leads to uncontrolled cell growth and proliferation.
Like other molecules considered non-druggable, Myc is very flexible, like a string of spaghetti. Without a distinct structure, it is very difficult to find small molecules that bind to it and inhibit it. Instead, Koehler has focused on targeting other proteins that have crucial associations with Myc.
So far, their work has yielded 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 activity. . The latter compound is now in early-stage clinical trials led by Kronos Bio, a company co-founded by Koehler.
“Going after Myc’s neighboring proteins has turned out to be a more tractable strategy,” says Koehler. “We are now applying what we have learned not only to other transcription factors, but to other non-pharmaceutical targets, such as RNA-binding proteins or cytokines, which are not druggable for various reasons.”
Spinning his research into companies that could use it to develop potential therapeutics is a key goal of Koehler’s lab. He also co-teaches a course on the science and business of biotechnology, which focuses on developing ways to scale up technologies developed in academia.
“When I was a graduate student at Harvard, I never thought I would care about this piece of translation, but this is part of the lifeblood of the MIT community,” says Koehler. “If your technology or your idea has legs, we spend a lot of time here in the MIT community thinking about how to implement that technology. That’s another reason I feel a kinship with engineers, even though I don’t have a degree engineering officer. Engineers are very focused on trying to make sure their idea or invention is ready to roll out into the wider world and make an impact.”