Finding molecules with the potential to treat human diseases is a major challenge for health researchers. In an article recently published in the scientific journal Bioorganic & Medicinal Chemistry, researchers from the Center for Medicinal Chemistry (CQMED) at Unicamp presented a series of techniques involving enzymatic assays, assays on living cells and computational modeling with the aim of speeding up the discovery of new molecules. The study used a protein related to tumor growth as a model and, after investigating more than 350 different molecules, the researchers arrived at a candidate molecule to function as an inhibitor of this protein.
According to Micael Cunha, one of the authors of the work and a postdoctoral fellow at CQMED, the great novelty of the work consisted of presenting to the scientific community a package of tools such as assays, reagents and new inhibitory molecules to study the protein. “We presented a series of techniques for discovering new drugs that are ready to be used to study the MKK3 protein and we also published a new class of specific inhibitors for this target protein”, comments Cunha.
Previous studies have already pointed to the MKK3 protein as an important factor in the survival and proliferation of tumor cells. By inhibiting the action of this protein, it is possible to stop the growth of tumors. Combining this approach with other therapies significantly increases the efficiency of antitumor treatment. In the midst of the process, CQMED researchers used cloning, a technique that consists of copying the genetic code of a protein to be synthesized in another organism that is easy to manipulate, such as bacteria. This made it possible to produce the protein in the laboratory and thus test the inhibitory action of various compounds.
The most promising molecules went through an optimization process, having their chemical structure changed in order to increase inhibitory efficiency in the specific case of the MKK3 protein. “We believe that these procedures will pave the way for a new generation of MKK3 inhibitors with optimized potency and selectivity, allowing researchers to discover the specific functions of this protein in cell biology”, wrote the authors of the work, carried out at Unicamp.
After investigating hundreds of different molecules, CQMED researchers identified a very promising one. This molecule, with a complicated name, pyrazol[3,4-d]pyrimidine, was shown to be capable of recognizing the MKK3 protein and inhibiting its activity. Although it does not yet have all the characteristics necessary to serve as a medicine, this new molecule has potential as a prototype for future research dedicated to investigating the cellular mechanisms of cancer, promising to become an important tool for advancing knowledge in the area.
There is a long way to go from the identification of a promising molecule to its approval for clinical use in patients, something that takes, on average, around 15 years. For this reason, any strategy capable of improving the investigation and reducing this time proves to be important for accelerating research in the area. “The multidisciplinary approach helps a lot to find new paths and new modes of analysis. In this sense, we have an advantage because we bring together specialist researchers in the same laboratory dedicated to carrying out work located at the interface between chemistry and biology”, points out Rafael Couñago, scientific coordinator of CQMED and researcher at the University of North Carolina (United States) .
“Now that we have a well-structured sequence of experiments to study this protein, we intend to test a larger number of compounds in order to select those with desirable characteristics, carry out chemical modifications and continue with new rounds of tests to evaluate potency, specificity, toxicity and capacity of the molecule to interact specifically with MKK3”, said Cunha.
Access the article: “Discovery of pyrazolo[3,4-d]pyrimidines as novel mitogen-activated protein kinase 3 (MKK3) inhibitors”. Bioorganic & Medicinal Chemistry, v. 98, 2024.
About CQMED
The Medicinal Chemistry Center (CQMED), located at the Center for Molecular Biology and Genetic Engineering (CBMEG), is linked to the Coordination of Centers and Nuclei (Cocen) at Unicamp, in Campinas (SP). The center specializes in the early stages of developing new drugs and new molecular diagnostics. To this end, it developed a platform for discovering molecules that inhibit specific targets related to human diseases. CQMED, founded in 2015, is currently accredited as an Embrapii unit (Brazilian Industrial Research and Innovation Company) and is part of the National Institutes of Science and Technology Program (INCTs) of the National Council for Scientific and Technological Development (CNPq).
