The human proteome is vast and, to the chagrin of drug developers, largely out of reach. Of the tens of thousands of proteins that perform our cells’ various functions, only about 15% can be accessed with conventional small molecules and antibody drugs.
Chemical biologist Lynn McGregor is helping to change those stats. Throughout her academic training and nascent career in industry, she has developed expertise in a range of technologies that could help open up the possibilities of the proteome.
As a postdoctoral fellow in Kevan Shokat’s lab at the University of California, San Francisco, McGregor took on one of the most daunting drug targets out there, KRAS. The protein is notorious for its frequent involvement in cancer—and for the decades drug developers have spent trying to crack it.
Shokat’s lab had already succeeded in finding the first tool compound to block a mutant form of KRAS called G12C. McGregor was tasked with blocking another KRAS variant, G12D.
Research at a glance
McGregor helped develop a quick test for whether a particular E3 ligase can spur a disease-causing protein to be tagged by ubiquitin for breakdown. An E3 ligase's cysteine side chain (SH) is modified by tacking a ligand for a protein of interest onto it. In a process called electroporation, an electrical field is applied to cells to allow the complex inside, after which researchers can track whether the protein of interest is tagged for degradation by ubiquitin.
Credit: Yang H. Ku/C&EN
In the end, she didn’t succeed (though it’s worth noting that to date no one has been able to develop a KRAS G12D inhibitor). “There’s probably thousands of people with a failed RAS project, and I’m one of them,” McGregor jokes.
But just tackling such a challenging endeavor shows McGregor’s mettle, Shokat says. “It takes a special scientist willing to take on these kinds of projects because starting out you know the odds are against success.”
McGregor has continued to explore new and difficult frontiers of drug discovery. After her postdoc, she took a job in Novartis’s chemical biology group, where one of her projects has been to improve the design of protein degraders—small-molecule drugs that break down, rather than simply block the activity of proteins. These bifunctional small molecules feature one end that binds to a protein of interest and another end that binds to an E3 ligase, which is responsible for recruiting the other players in the cell’s protein disposal system.
Researchers have spent the past several years trying to work out the rules for constructing these complex molecules, which to date have largely been fashioned through trial and error. McGregor, along with Novartis colleagues and their partners at the University of California, Berkeley, is helping develop a more rational approach.
The collaborators recently tethered three types of E3 ligases to the blood cancer treatment dasatinib to understand how each affects the breakdown of a fusion protein, BCR-ABL. It turns out that the protein degrader featuring the natural product nimbolide was highly specific for that cancer-driver, while the two other E3 ligases either were inactive or didn’t break down the entire complex.
Given those differences, McGregor then began exploring easier methods for choosing the right E3 ligase. So far the field has focused on only a few of the hundreds of E3 ligases available, and Novartis scientists wanted an easy filter for the best ligase for a particular protein. In soon-to-be-published work, McGregor and a small team of interns from Dana-Farber Cancer Institute came up with a method that uses simple chemistry to directly modify an E3 ligase and put it back into cells to ask whether it causes a protein of interest to be degraded.
It’s this type of work, accomplished with many different partners, that has made her stand out within a big company like Novartis. “Lynn’s humble and collaborative nature provides balance with her steely determination to advance chemical biology at Novartis,” says John Tallarico, head of chemical biology at Novartis Institutes for BioMedical Research. “Her talents include not only scientific acumen but that special people ability to bring experts from different disciplines together at a high level to get important questions answered.”
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