Thalidomide Goes From Infamy to Innovation
Cells routinely dispose of old or damaged proteins, breaking them down into their essential parts and reusing the components to build new proteins. Twenty years ago, researchers first proposed an idea to harness this system in a targeted way using chimeric
molecules — in which fragments of two different molecules are joined together to create an entirely new one. Like a two-headed snake, one end of the chimera binds to a protein of interest and the other end to the protein-degrading machinery, thereby
forcing destruction of the target.
"At the time, researchers had shown this could work in artificial systems, but not at the concentrations or with molecules that were likely to become drugs," said Nathanael Gray, PhD, a chemical
biologist at Dana-Farber. "It was basically a neat trick in the realm of chemical biology."
But the field began to shift in a big way about a decade later. Two research teams, one led by Ebert and another by Dana-Farber's William Kaelin, MD, a 2019 Nobel Laureate,
were studying a new blood cancer drug. Known as lenalidomide, it is a chemical cousin of thalidomide, the infamous morning sickness
pill recalled in the 1960s due to the devastating birth defects it inflicted on thousands of children. With strict regulations in place, thalidomide and its relatives had been repurposed as safe and effective treatments for multiple myeloma as well
as other blood cancers. Precisely how the drugs worked, however, remained unknown.
Some pivotal clues emerged when Ebert, Kaelin, and their colleagues reported in 2014 that lenalidomide targets two proteins, IKZF1 and IFZF3, for destruction. When the drug is present, these proteins are recognized by a member of the cells' protein-recycling
system and flagged for degradation.
Remarkably, IKZF1 and IKZF3 are among a large group of regulatory proteins called transcription factors, which are often key drivers of tumor growth. Although these regulators are widely viewed as linchpins of modern cancer therapy, they are notoriously
difficult to design drugs against. With their smooth, featureless surfaces, they are like tiny cue balls — devoid of any nooks or crannies where a drug might bind.
"When this mechanism was discovered, people began to believe that protein degradation could become a more generalized approach," said Gray. "With a successful drug already on the market, nobody could say it would never work — and that really galvanized
Detailed studies of the thalidomide-like drugs are now helping to chart another critical path: how to purposefully design more transcription-factor-demolishing drugs. IKZF1 and IKZF3 contain a characteristic molecular pattern, known as a C2H2 zinc finger.
It turns out that in humans, hundreds of other transcription factors harbor this same motif, too.
By carefully dissecting how the thalidomide-like drugs interact with their molecular partners (also called "substrates"), Ebert and his colleagues, along with Dana-Farber's Eric Fischer, PhD,
and his team, are working out how other zinc-finger-containing transcription factors might be placed in the crosshairs of protein degraders.
"It's critically important to understand on a molecular level how these molecules recruit their substrates and why some work and some don't," said Fischer. "With this knowledge, we can use sophisticated computer modeling to help us uncover even more potential
His work is not only helping spur the design of powerful new cancer drugs, but also shedding light on why the tragic outcomes wrought by thalidomide — children with severely shortened, malformed limbs as well as other birth defects — were not detected
earlier during its clinical development.