Analysis of genetic mutations linked to diseases such as cancer has uncovered many potential drug targets. However, a significant number of these proteins are considered “unusable”, mainly because their structure is too flexible for a small molecule drug to bind to.
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 deactivate them or reduce their impact. This approach has already yielded a potential cancer drug that is in the early stages of clinical trials, with more in the pipeline.
“In our lab, we are thinking about several molecular strategies to disrupt the function of the transcriptional regulatory network in which a target resides. Sometimes it attacks the target directly, and sometimes it takes advantage of partner proteins,” explains Koehler, who is also a member. from the Koch Institute for Integrative Cancer Research at MIT.
Koehler, who trained as a chemical biologist, wears many different hats as the leader of his research group. Every day she can focus her attention on studying the biology of protein interactions, designing new tools to analyze these interactions, developing chemical approaches for designing new drugs or building startups and collaborating with pharmaceutical companies on potential drug compounds.
“The measure of MIT’s success is the impact you have, whether it’s writing papers or translating your work around the world,” she says. “Increasingly, we are 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 tougher goals.
“Biologically Interesting Problems”
Koehler, who grew up in Portland, Oregon, was 4 when nearby Mount St. Helens erupted in 1980, an event that both terrified her and sparked her interest in science.
“Every year, to help me overcome the trauma of living next to a volcano, my parents would take us to the mountains,” Koehler recalls. “Each year you could go a little further, but at first it was just utter devastation. Later, you could see fields sprouting with flowers and life was starting to come back.
Seeing this devastation and recovery up close inspired an interest in geology and later other scientific fields, especially biology. At Reed College, she began her pre-med but soon realized she was more interested in the molecular aspects of biology than becoming a doctor.
During her freshman year at Reed, Barbara Imperiali, then a Caltech chemistry professor (and now an MIT faculty member), came to give a talk that Koehler remembers as the event that inspired her to go to university and pursue a career in academia.
“She came to Reed and gave this incredible talk in a field called bioorganic chemistry. She would apply her skills as a chemist to biologically interesting problems, then design new types of molecules and tools. And I thought, I want to be like her when I grow up,” Koehler says. “That conference was one of the solidifying moments for me to realize, oh, I want to go do a PhD.”
After spending his first year of graduate school at Caltech, Koehler moved to Harvard University to complete his doctorate, working with Stuart Schreiber, professor of chemistry. There she began developing a technology that her lab at MIT now uses, which consists of microarrays of small molecules that can be screened for activity against target proteins.
Around the time she completed her doctorate, Schreiber, MIT professor Eric Lander and others were planning 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 newly discovered genes that appeared in the genomic map. Koehler’s work developing technology to analyze protein properties 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 provided insight into the role of proteins linked to specific diseases and helped identify drugs that could target them. In 2013, she decided she was ready to move into a tenure-track position and began applying for faculty positions, including one in MIT’s Department of Biological Engineering. Her research also caught the interest of the management of the Koch Institute and she ended up being hired as an assistant professor of biological engineering, with her laboratory at the Koch Institute.
Tackle 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. “Bioengineering was by far the best fit for me given that chemical biologists often like to think quantitatively.”
In his lab at MIT, which is populated by chemists, biologists, engineers, and computer scientists, Koehler focuses on finding ways to drug certain non-drug targets. Much of his work focuses on a protein called Myc, which is overexpressed in about 70% of cancers. Myc is a transcription factor, which means it controls the expression of many other genes. Overexpression of Myc leads to uncontrolled cell growth and proliferation.
Like other molecules considered non-medicinal, Myc is very flexible, like a strand of spaghetti. Without a distinct structure, it is very difficult to find small molecules that will bind to it and inhibit it. Instead, Koehler focused on targeting other proteins that have crucial partnerships with Myc.
So far, his 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 activity. The latter compound is currently undergoing preliminary clinical trials by Kronos Bio, a company co-founded by Koehler.
“Tackling Myc-neighbouring proteins turned out to be a more manageable strategy,” says Koehler. “We are now applying what we have learned not only to other transcription factors, but also to other non-drug targets like RNA-binding proteins or cytokines, which are non-drugable for different reasons.”
Spinning his research into companies that could use it to develop potential therapies is a key goal of Koehler’s lab. She also co-teach a course on the science and business of biotechnology, which focuses on developing ways to expand the use of developed technologies in academia.
“When I was a graduate student at Harvard, I never thought I would care about this piece of translation, but it’s part of the soul of the MIT community,” Koehler says. “If your technology or idea has legs, we spend a lot of time here in the MIT community thinking about how to deploy that technology. This is another reason why I feel close to engineers, even though I don’t have an official engineering degree. Engineers are very focused on trying to make sure their idea or invention is well placed to be deployed around the world and have an impact.
#Angela #Koehler #takes #toughest #drug #targets