A study published this Thursday (23) in the Journal of Medicinal Chemistry describes the development of an unprecedented molecule capable of inhibiting the VRK1 protein, involved in maintaining DNA integrity and cell proliferation in certain cancers, including breast, prostate, ovary, intestines and gliomas (in the brain).
This new molecule serves as a tool to investigate cellular and systemic effects of VRK1 inhibition in both healthy and tumor cells. Furthermore, the study consolidates VRK1 as a potential therapeutic target for several types of cancer and opens the horizon for the development of new treatments.
The work was led by researchers from the Center for Medicinal Chemistry (CQMED) at the State University of Campinas (Unicamp) and Aché Laboratórios Farmacêuticos and involved collaborators from Brazil, the United Kingdom, Sweden, Germany and the United States. This is the result of five years of research focused on this target protein, which plays a leading role in the proliferation of certain types of cancer.
Tumor cells have mutations that cause them to multiply quickly and end up accumulating errors in the genome. VRK1 is a protein kinase (a type of enzyme that modifies other proteins by adding phosphate molecules, in a process known as phosphorylation). It participates in the cellular response that detects and repairs this damage to DNA, therefore enabling the proliferation of mutated cells. The absence of VRK1 causes cells to accumulate errors in their genomes, leading to cell death. In tumor cells, this kinase is produced in greater quantities.
“In this work, we show that when VRK1 is inhibited in cells, errors are not repaired and they end up dying, as the accumulation of damage is too great”, explains Rafael Couñago, researcher at CQMED and author of the article.
The inhibitory molecule, derived from dihydropteridinone, was initially identified by the CQMED team and subsequently developed by Aché scientists. The researchers conducted assays designed specifically to demonstrate the molecule's action on the protein within the cellular environment.
“This is the first time that we have described a molecule that inhibits VRK1 in a potent, selective and highly characterized manner in the cellular context”, adds Hatylas Azevedo, director of R&D at Aché Laboratórios Farmacêuticos and author of the study.
Open Science
Over the five years, the project followed the premises of open science advocated by the Structural Genomics Consortium (SGC), an international consortium of research centers that is a partner of FAPESP in supporting CQMED and studies little explored human proteins (read more at: agencia.fapesp.br/20790).
The group received funding through the Partnership for Technological Innovation (PITE) program and the National Institute of Science and Technology (INCT) Open Access Medicinal Chemistry Center. Currently, the partnership is part of the CQMED Embrapii Unit's project portfolio.
“The work was highly collaborative, with international partnerships, universities and the Brazilian pharmaceutical industry”, points out Couñago. Until now, it has had a basic research character, but the results can be used in applied science. “This work can serve as a basis for companies, universities and scientists around the world to investigate the role of VRK1 in the tumor context, as well as use this molecule as a starting point for modifications that turn it into a drug”, comments Azevedo.
Although the results are promising, several tests are still needed before stating that it is a new drug for the treatment of cancer.
In the human genome there are around 530 described kinases, of which science is only well aware of 80. For functional knowledge of these enzymes, it is important to develop inhibitors that act selectively for each of them. These inhibitors can serve as probes to advance the understanding of these enzymes, allowing them to be characterized functionally.
The article Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε can be accessed at: https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.3c02250
*With information from CQMED.
Source: CNN Brasil
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