How to find anti-cancer agents

Researchers at the Paul Scherrer Institute PSI and the Italian Institute of Technology IIT have developed a novel substance that disables a protein in the cell skeleton, leading to cell death. In this way, substances of this type can prevent, for example, the growth of tumours. To accomplish this, the researchers combined a structural biological method with the computational design of active agents. The study appeared in the journal Angewandte Chemie International Edition.

Have crystals grown, or not? Tobias Mühlethaler checks his protein solutions in the crystal production facility at PSI.
(Photo: Paul Scherrer Institute/Mahir Dzambegovic)
The research team in front of SLS (from left): Andrea Prota, Tobias Mühlethaler, and Michel Steinmetz
(Photo: Paul Scherrer Institute/Mahir Dzambegovic)
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The cell skeleton, also called the cytoskeleton, pervades all of our cells as a dynamic network of thread-like protein structures. It gives cells their form, aids in the transport of proteins and larger cell components, and plays a crucial role in cell division. The central building block is the protein tubulin. It arranges itself into tube-shaped structures, the microtubule filaments.

Active agents that attach to the cell skeleton are among the most effective drugs against cancer. They block tubulin, and thus prevent cell division in tumours. PSI researchers, in collaboration with the Italian Institute of Technology in Genoa, have now developed another potent substance that disables tubulin. The have dubbed it ‘Todalam’.

"Todalam prevents tubulin from arranging itself in the form of microtubule filaments," explains first author Tobias Mühlethaler, who co-designed and studied the substance as part of his doctoral research at PSI. "The protein remains as if frozen in a structure that doesn't fit into microtubules."

Rationally designed

There are typically two different approaches for developing new drugs: Researchers can test an enormous number of molecules to fish out the ones that appear promising, or they can specifically design chemical molecules that achieve the desired effect. The PSI and IIT researchers chose the second path, which is often more difficult.

In doing this, they were able to build on their own groundwork, research in which they had already located places in tubulin where molecules can dock especially well. These are the so-called binding pockets, of which they found 27. In addition, the researchers identified 56 fragments that bind to these sites. This work, too, had been published earlier in Angewandte Chemie International Edition.

In the current study based on this prior work, the researchers initially selected a newly discovered binding pocket on tubulin. They used computational design to combine the structures of three molecular fragments, which preferentially dock at this point, into a single chemical compound, and then they synthesised it in the laboratory. "By combining the three fragments into one molecule, we hoped to enhance the effect, since the new molecule fills the binding pocket better," says Michel Steinmetz, head of the Laboratory of Biomolecular Research at PSI.

Using measurements at the Swiss Light Source SLS, the researchers checked to see how well the molecule actually fits into the binding pocket. In two further cycles, they improved the substance until they arrived at Todalam. "With relatively simple chemistry, we managed to get to a potent compound," proudly says Andrea Prota, a scientist in the Steinmetz group who collaborated closely with Mühlethaler.

Simple chemical structure

In cell cultures, the researchers demonstrated that Todalam kills cells. No wonder, since tubulin is essential for life. "The better a substance binds to a critical site in tubulin, the more toxic it is for the cells," Steinmetz explains. That makes Todalam a promising starting point for developing a drug.

The cytoskeletal inhibitors currently in clinical use are natural substances with large, complex structures and are therefore difficult to synthesise. The newly developed compound Todalam, on the other hand, can be produced in a simple chemical synthesis in the laboratory. "That also means that the compound could be produced in large quantities relatively easily," Steinmetz stresses.

Text: Paul Scherrer Institute/Brigitte Osterath

About PSI

The Paul Scherrer Institute PSI develops, builds and operates large, complex research facilities and makes them available to the national and international research community. The institute's own key research priorities are in the fields of matter and materials, energy and environment and human health. PSI is committed to the training of future generations. Therefore about one quarter of our staff are post-docs, post-graduates or apprentices. Altogether PSI employs 2100 people, thus being the largest research institute in Switzerland. The annual budget amounts to approximately CHF 400 million. PSI is part of the ETH Domain, with the other members being the two Swiss Federal Institutes of Technology, ETH Zurich and EPFL Lausanne, as well as Eawag (Swiss Federal Institute of Aquatic Science and Technology), Empa (Swiss Federal Laboratories for Materials Science and Technology) and WSL (Swiss Federal Institute for Forest, Snow and Landscape Research). (Last updated in May 2020)

Further information


Prof. Dr. Michel Steinmetz
Head of the Laboratory of Biomolecular Research

Paul Scherrer Institute, Forschungsstrasse 111, 5232 Villigen PSI, Switzerland
Telephone: +41 56 310 47 54, e-mail: [German, English, French]

Dr. Andrea Prota
Laboratory for Biomolecular Research
Paul Scherrer Institute, Forschungsstrasse 111, 5232 Villigen PSI, Switzerland
Telephone: +41 56 310 51 60, e-mail: [German, English, Italian]

Original publication

Rational Design of a Novel Tubulin Inhibitor with a Unique Mechanism of Action
Tobias Mühlethaler, Lampros Milanos, Jose Antonio Martínez, Thorsten Blum, Dario Gioia, Bibhas Roy, Andrea Prota, Andrea Cavalli, Michel O. Steinmetz
Angewandte Chemie International Edition, 11.04.2021 (online)


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