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 studied by the group is a potent inhibitor of the MPS1 protein, involved in the growth of solid tumors. The research results were published in the Journal of Medicinal Chemistry.
The work, conducted at the Center for Medicinal Chemistry at the State University of Campinas (Unicamp), has the support of the Foundation for Research Support of the State of São Paulo (Fapesp). The next steps involve improving the molecule and carrying out tests on laboratory animals and human tumor cells.
The research target – MPS1 (monopolar spindle kinase 1) – is a protein that belongs to the kinase class and plays a critical role in controlling cell division. Excessive expression 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 the action of MPS1.
Kinases, in general, are considered priority targets for drug development, as they regulate a series of important processes within cells.
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 target proteins reversibly, in dynamic equilibrium. The modification we made to this compound makes it bind definitively and this is an advantage for the development of a new drug, as there is a prolongation of the inhibitory action on the protein”, explains Rafael Couñago, researcher at Unicamp and author of the study.
When it comes to developing a new drug, the way the compound binds to the target protein has a lot of influence on the effectiveness of the treatment. Covalent bonding, if well planned, is a desired feature, as it ensures that the molecule does not move towards its target, which could impair the therapeutic effect. Among the drugs that establish this type of link are penicillin, omeprazole and aspirin, among others.
Currently, only eight kinase inhibitor drugs are known to covalently bind to the target. In the case of this research, the authors explored 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 favorable in terms of selectivity and potency when developing an inhibitory molecule with therapeutic potential, as it greatly reduces the chance that our molecule will bind to other kinases. [o que poderia causar efeitos adversos]”, explains Ricardo Serafim, who did his post-doctorate at Unicamp.
Currently, Serafim is a researcher at the University of Tübingen, in Germany, where he carried out an internship with support from Fapesp.
investigations
In order to get to the covalent inhibitory molecule, the researchers analyzed the three-dimensional structure of MPS1 in search of promising sites for the coupling of molecules. They then started looking for potential inhibitors in the Protein Data Bank (PDB), a public database maintained by an international organization called the Worldwide Protein Data Bank.
This initial selection, together with computer simulations, led to a set of three promising chemical series.
From this step, Serafim synthesized approximately 30 molecules to test them in enzymatic assays and identified a class of compounds with the desired inhibition mechanism for MPS1. The covalent bond was later confirmed by means of mass spectrometry and X-ray crystallography. “We tested the molecule in cell assays and saw that it is effective in treating cancer cells”, explains Serafim.
Usually, the experiments that differentiate covalent inhibitors from non-covalent inhibitors are quite complex and require different expertise. “We worked hard to prove that there was a covalent bond between compound and target. Being in a multidisciplinary center in Brazil capable of developing the enzymatic assay, mass spectrometry and X-ray crystallography helped a lot to accelerate this process”, emphasizes Couñago.
Now that the authors have identified a potent MPS1 inhibitor, they intend to improve some of the molecule’s properties before starting clinical trials.
“We were successful in the proof of concept. Now adjustments are needed, mainly in terms of reactivity, so that it becomes even more efficient in inhibiting the target protein”, concludes Serafim.
* With information from the Communications Office of the Center for Medicinal Chemistry.
Source: CNN Brasil
