Small molecules to treat big diseases

A molecular glue (in white) brings together two cell cycle regulators (purple an
A molecular glue (in white) brings together two cell cycle regulators (purple and blue) with an enzyme (green) that tags them as waste. Image credit: Georg Kempf/Thomä lab/FMI

Despite leaving behind thousands of deformed infants, thalidomide — and newer drugs derived from it — have proved effective cancer treatments. Researchers in the group of Nicolas Thomä at the FMI provided key insights into the mechanism of action of thalidomide-like drugs. Their work could help develop molecules that target and destroy disease-causing proteins, thus enabling the treatment of uncurable conditions.

In 1961, Australian doctor William McBride wrote a letter to The Lancet voicing concern about "severe abnormalities" — including shortened limbs, malformed hands and damaged internal organs — in babies born from women who had taken a drug called thalidomide during pregnancy.

McBride’s concerns about thalidomide, which was being used in dozens of countries for treating morning sickness in pregnant women, were soon confirmed by other doctors in Europe. The drug was banned in winter 1961, but by that point it had affected thousands of babies.

Despite the tragic legacy, thalidomide and its derivatives have later resurfaced as effective treatments for some cancers. How these drugs work to slow cancer’s progression remained a mystery until the early 2010s, when scientists discovered that thalidomide can trigger the destruction of specific proteins that are overactive in cancer cells.

In the past ten years, researchers led by structural biologist Nicolas Thomä at the FMI have deciphered the molecular and atomic mechanism through which thalidomide binds to and destroys these proteins.

Their findings have opened the door to a new, potentially revolutionary strategy in the development of treatments for tough diseases such as cancer. "Our results suggest that novel drugs can be developed for applications that were previously unthinkable," Thomä says.

Molecular glues

For a long time, scientists thought that two proteins would bind if they had complementary shapes that fit exactly into one another — like a key into its lock.

Thomä’s work has contributed to upend this idea, showing that some keys alone can’t open specific locks unless a ’molecular glue’ is present. Molecular glues are molecules that stick together two proteins that normally wouldn’t interact. They achieve this by changing the surface properties of their target proteins.

Thalidomide acts as a molecular glue: it binds to specific target proteins, including some that turn genes on and off, and makes them come together with an enzyme that causes the target to be broken down by the cell’s protein-degradation machinery.

Essentially, thalidomide can promote the degradation of disease-causing proteins, leading cancer cells to die. But thalidomide can also degrade proteins that are important during embryonic development, which explains why the drug caused congenital conditions when taken during the first trimester of pregnancy.

Next-gen therapeutics

Using a powerful technique for imaging structures at the individual atom level, Thomä and his team have been able to observe thalidomide and its derivatives in action, linking target proteins to the enzyme that marks them as waste.

In recent years, Thomä’s team has provided key insights into how thalidomide and other molecular glues target harmful proteins and release them for degradation. "That opened the door to an entirely new strategy for going after these types of targets," Thomä says. (Learn more about this work in the video below.)

About the video: Structural biologist Nicolas Thomä talks about his fascination with proteins and his work on "molecular glues".

For his groundbreaking work on targeted protein degradation, in 2022 Thomä received the Otto Naegeli Prize for Medical Research, one of Switzerland’s most prestigious scientific awards.

The revolutionary mode of action of thalidomide is now leading the way for the next generation of therapeutics — small molecules that can trigger the breakdown of disease-causing proteins on demand. Many of these molecules have been found by chance, but now researchers are racing to discover and develop more.

By revealing how molecular glues function, Thomä’s work could help reach an ambitious goal: find molecules that can target any protein, thus enabling the treatment of uncurable diseases.