Scientists from Brazil and Germany have taken an important step in the search for a compound that could lead to a new cancer treatment. The molecule the group studied is a potent inhibitor of the MPS1 protein, which is involved in the growth of solid tumors. The results of the poll were published yesterday (15). number Journal of Medicinal Chemistry.
The work is being carried out at the Center for Medicinal Chemistry (CQMED) of the State University of Campinas (Unicamp), with the support of FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo). Next steps include optimizing the molecule and performing tests on laboratory animals and human tumor cells.
The research target – MPS1 (monopolar spindle kinase 1) – is a protein belonging to the class of kinases that plays an important role in controlling cell division. Overexpression of this protein has been associated with a variety of solid tumors, including breast, pancreas, glioblastoma, and neuroblastoma. For this reason, many research groups are looking for molecules capable of inhibiting MPS1 action.
Kinases, in general, are priority targets for drug development, as they regulate a series of important intracellular processes. In this work, the scientists designed and tested a small molecule that covalently binds to the MPS1 protein (a stable bond type due to the sharing of electrons between the two atoms).
“In general, the compounds bind to the target proteins reversibly, in a dynamic equilibrium. Explains Rafael Coniago, researcher at CQMED and author of the study.
When it comes to developing a new drug, the way the compound binds to the target protein has a significant impact on the effectiveness of the treatment. Covalent bonding, if well planned, is a desirable feature, as it ensures that the molecule does not move towards its target, which may impair the therapeutic effect. Among the drugs that demonstrate this type of association are penicillin, omeprazole and aspirin, among others.
Currently, only eight kinase inhibitors are known to covalently bind to the target. In the case of this research, the authors discovered an unusual feature of MPS1, which is the presence of a cysteine amino acid residue at a specific position.
Of the more than 500 kinases encoded by the human genome, only five have this characteristic. “This is advantageous in terms of selectivity and efficacy when developing an inhibitory molecule with therapeutic potential, as it greatly reduces the chance of our molecule binding to other kinases. [o que poderia causar efeitos adversos]Ricardo Seraphim, who did postdoctoral work at CQMED with support from FAPESP, explains. Currently, Seraphim is a researcher at the University of Tübingen, Germany, where he also conducted an internship with the support of the institution.
In order to gain access to the covalent inhibitory molecule, the researchers analyzed the 3D structure of MPS1 in search of promising sites for molecular coupling. Then they began searching for potential inhibitors in the Protein Data Bank (PDB), a public database maintained by an international organization called the Global Protein Data Bank.
This initial selection, combined with computer simulations, led to a set of three promising chemical series. From this step, Seraphim assembled approximately 30 molecules for testing in enzymatic assays and identified a class of compounds with the desired inhibition mechanism of MPS1. The covalent bond was subsequently confirmed by mass spectrometry and X-ray crystallography. “We tested the molecule in cell assays and saw that it is effective in treating cancer cells,” Seraphim explains.
Experiments distinguishing between covalent and non-covalent inhibitors are usually very complex and require different experiences. “We have worked hard to prove the existence of a covalent bond between the compound and the target. Being in a multidisciplinary center in Brazil capable of developing enzymatic assay, mass spectrometry and X-ray crystallography has helped a lot to speed up this process,” confirms Coniago.
Headquartered in the Unicamp Center for Molecular Biology and Genetic Engineering (CBMEG), CQMED is a unit of the Brazilian Corporation for Industrial Innovation (Embrapii) and the National Institute of Science and Technology (INCT) with the support of FAPESP, Coordinating the Improvement of Higher Education Personnel (CAPS) and the National Council for Scientific and Technological Development (CNSTD) CNPq).
Now that the authors have identified a potent MPS1 inhibitor, they intend to improve some of the molecule’s properties before clinical trials begin. “We succeeded in proof-of-concept. Now modifications are needed, mainly in terms of interaction, so that it becomes more efficient at inhibiting the target protein,” concludes Seraphim.
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