This is a very early stage of development under laboratory conditions, the first step on a long road toward clinical trials. However, because cancer cells can become resistant to existing drugs over time, the search for new molecules capable of blocking their growth is becoming increasingly important in the fight against tumors.
The results were published in Scientific Reports, a journal within the Nature publishing group. It is a peer reviewed, open access journal in multidisciplinary science and, by impact factor, is ranked among the top third of journals in its field.
Existing therapies and the problem of tumor cell resistance
BRAF is a gene that carries the “instructions” for a protein involved in controlling cell growth and division. When a mutation occurs, that protein can behave as if its switch has jammed, staying permanently on and sending cells signals to divide and grow even when there is no need. Such a disruption can trigger tumor formation and accelerate progression. The most common change, BRAF V600E, occurs in about half of melanomas and in a significant share of papillary thyroid carcinomas, which is why BRAF status is now considered an important marker that helps in understanding the disease and selecting targeted therapy.
Drugs that target BRAF already exist, but in some patients the tumor can become resistant over time, or side effects may occur. That is why the search for new molecules continues. Researchers are looking for new “candidates” that could one day be more effective or safer. Because BRAF mutations appear in multiple tumor types, progress in this area could have broader impact than a single diagnosis.
In the new paper published in Scientific Reports, the researchers describe how they designed and produced nine new molecules, labeled S1 to S9, which, in laboratory tests, can “dampen” this jammed switch. First, using computational modeling, they estimated how these molecules might fit into the target site on the BRAF V600E protein, like a key trying to block a lock, and then they synthesized them in the laboratory.
From computer to test tube, the journey of one molecule
Two sets of experiments followed. In the first test, performed on the protein itself, they measured how well the compounds reduced its activity, comparing them with the already known drug sorafenib. In the second step, they examined effects on melanoma (A375) and thyroid cancer (TPC 1) cell lines, tracking whether tumor cell growth slowed in culture.
“In the protein level test, we saw that two compounds stood out. Molecule S4 reduced BRAF V600E activity by about 91%, and S1 by about 87%. For comparison, the reference drug sorafenib was about 94% in the same test. That is why we focused on S4 and S1 as the most promising candidates and ran more detailed computer simulations to see how stably they bind to the target,” explains Jurica Novak, PhD, one of the lead authors from RBI.
Those simulations were carried out at RBI, with a key role played by national research infrastructure and access to the Supek supercomputer, provided by the University Computing Centre (SRCE) of the University of Zagreb. Computational methods in projects like this act as a kind of atomic level “magnifying glass,” showing how a molecule behaves within the protein’s active site and helping narrow the selection to the most promising compounds before more expensive and longer experiments.
Still, despite the encouraging numbers in the protein assay, the cell based results are a reminder of how long the path to a drug is. The new compounds did slow the growth of tumor cells in culture, but effects in cell lines are not, in any way, proof that these substances would work in the human body.
Why does this research matter for future therapies?
Because cancer cells can, over time, “learn” to bypass existing drugs and become resistant, the search for new molecules must not stop. Even when today’s therapy works well at first, some tumors can adapt, change how they receive signals, or activate other growth pathways, and then the drug is no longer effective enough.
“The BRAF V600E mutation may sound like a dry technical term, but in reality it represents a diagnosis, a therapy that does not work well enough, a family going through a difficult period,” says Novak. “That is why it is important to develop new molecules and approaches, because medicine still does not have answers for every patient,” emphasizes Jurica Novak, PhD, from RBI.
Every new chemical compound that shows, in the lab, that it can hit an important “growth switch” such as BRAF V600E adds another option to the future anti cancer arsenal. This research does not deliver a finished drug, but it expands the catalogue of promising molecules from which therapies may one day be developed that last longer, have fewer side effects, and remain effective even when a tumor tries to “switch strategies.”
The work was carried out by an international team of scientists from India, Saudi Arabia, and Croatia. The computational part of the research was led by Jurica Novak, PhD, from RBI, and complex simulations used the national Supek supercomputer. On the Croatian side, the research was funded by the Croatian Science Foundation (project IP-2022-4658), while the cost of publishing the paper in open access was covered by the Saudi university KAUST.
“I would like to emphasize that projects like this show the real value of investing in science and research infrastructure. When public funds enable researchers to access advanced technologies such as supercomputers, it creates space for innovations that would otherwise be beyond our reach. In this case, the combination of international collaboration, Croatian Science Foundation project support, and the availability of the Supek supercomputer enabled us, in a relatively short time, to identify molecules that could one day become new therapeutic candidates. This is the best example of how strategic investments in science can generate results that are not only an academic contribution, but potentially also the foundation of future medical solutions,” concludes Jurica Novak, PhD, from RBI.
