A new approach increases the effectiveness of cancer treatment
Researchers at the Dana-Farber Cancer Institute, working under the guidance of Dr. James Bradner, have developed a promising new targeted cancer treatment method that, unlike traditional approaches, not only blocks the activity of pathological proteins in cells, but also destroys target protein molecules.
The aim of developing a new strategy was to overcome the resistance of tumors to treatment, which develops after malignant cells find ways to avoid exposure to the drug to which they initially reacted. One of the reasons for the development of resistance is that pathological proteins of tumor cells often perform many functions, whereas targeted drugs inhibit only one or several of them. Traditional drugs leave cells the opportunity to adapt and find alternative mechanisms that ensure their growth and division.
Therefore, the authors devoted their work to the search for methods that ensure the physical destruction of target proteins, and not only the suppression of their activity. This approach involves the involvement of a natural intracellular protein destruction system. Worn-out or unnecessary protein molecules to be destroyed are marked with a special label, which is a ubiquitin protein molecule. The ubiquitination process is carried out by three enzymes E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme) and E3 (ubiquitin ligase). After ubiquitination is completed, the labeled proteins enter the membrane vesicles known as proteasomes, where their enzymatic cleavage occurs.
In order to use this system in the destruction of cancer proteins, the authors created a chemical adapter, thanks to which a targeted drug binds a target protein molecule directly to one of the components of the protein destruction system. The result of this is the rapid and complete destruction of the target protein.
The researchers tested prototypes of new drugs, which they named "degronimids" ("degronimids") on leukemic cells. They started with the drug JQ1, which inhibits BRD4, a protein that regulates the expression of malignant growth genes. An adapter made of phthalimide, a chemical derivative of the drug thalidomide, was attached to the JQ1 molecule. The structure of such an adapter ensures its strong binding to the enzyme ubiquitin ligase.
When exposed to JQ1-phthalimide conjugate, called dBET1, on leukemic cells, the BRD4 protein included in them was completely destroyed in less than an hour. The authors believe that this is a demonstration of the possibility of using such conjugates in the treatment of cancer without the risk of developing resistance of tumor cells to therapy.
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Crystal structure of dBET1 (yellow sticks) bound to BRD4(1) (yellow ribbon),
superimposed on the structure of JQ1 (silver sticks) associated with BRD4 (silver ribbon).
To assess the selectivity of the action of dBET1, the researchers measured the amount of all proteins in leukemic cells before and two hours after exposure to the drug. It turned out that only three out of 7,000 proteins are degraded, namely BRD-2, -3 and -4, which indicates the exceptional specificity of the new approach.
After that, dBET1 was tested on mice with a severe aggressive form of human leukemia. As well as in laboratory tests, the introduction of dBET1 to animals provided rapid destruction of the BRD4 protein in malignant cells and a powerful antileukemic effect, accompanied by only a small number of registered side effects.
As an alternative, the authors synthesized a molecular complex that provides a junction between the mechanism of protein degradation and the SLF compound, the target of which is the FKBP12 protein. Exposure to SLF modified by this complex for several hours ensured almost complete destruction of the FKBP12 protein in leukemic cells.
Currently, researchers are developing derivatives of experimental drugs suitable for clinical trials. They hope that in the future their proposed strategy will help in the fight against various types of cancer and other diseases based on genetic mechanisms.
Article by Georg E. Winter et al. Phthalimide conjugation as a strategy for in vivo target protein degradation is published in the journal Science.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Dana-Farber Cancer Institute:
New chemical technology boosts potency of targeted cancer therapy.
25.05.2015