[China Pharmaceutical Network Technology News] In the United States, nearly 1.7 million people are diagnosed with cancer each year, and half of them have different versions of the p53 gene mutation, indicating how important the conventional protein p53 is in preventing cancer. It sounds the alarm to kill DNA cells and prevents them from becoming cancerous, which is why it is called the "genomic guardian."
It is large and soft, and it is difficult to track this molecular deformer with standard imaging tools. As a result, computational biologist Amaro of the University of California, San Diego switched to a supercomputer. She inserts a new X-ray snapshot of the p53 fragment and enhances the program to produce a video of each of the 1.6 million atoms of the protein at the microsecond (millionth of a second) level, so the continuity of the atomic level requires super The computer calculates about 1 month. She looks at the four copies of p53 that are connected to each other and then wrapped around a DNA strand. This is an important "dance" that p53 protein "jumps" before the message of cell self-destruction.
Amaro is not only interested in the behavior of healthy p53: she wants to understand the effects that p53 mutations may cause. In dozens of simulations, she and her colleagues tracked how ordinary p53 mutations further made this already soft-stable protein more unstable, distorting it and preventing it from binding to DNA. Some simulations have revealed additional content: or can provide support for a potential drug. Sometimes, the mutant protein core forms a small gap. When Amaro added virtual drug molecules to the model, the drug stayed in the crack, making p53 stable enough to return to normal function.
For Amaro and some other researchers, computer simulation has inspired. "A long-term dream in the field of cancer biology is to find small molecule drugs that can restore p53 activity," Amaro said. "We are very excited about this."
Great return
Conventional proteins are the most studied proteins in the scientific field and are also the focus of pharmaceutical companies. However, among the dozens of p53 drugs currently being developed, most drugs are only trying to improve the level of healthy p53. Although research in this area has been going on for decades, no drugs have yet entered the market.
Amaro's work demonstrates the progress that some scientific laboratories and small companies have used to target p53 in new ways: to save it after it gets sick. They are looking for drugs that bind to p53 and support the mutant p53 protein, allowing them to restore shape and function and perform routine tasks. One of these drugs has passed initial human safety testing, and a more advanced clinical trial is now underway in Europe. Other potential drugs are approaching human clinical trials. If clinically successful, they will significantly change the face of cancer treatment, in addition to other misfolded protein diseases, even Alzheimer's disease.
However, it won't be easy. Restoring the normal function of a variant protein is more difficult than the strategy of blocking only one protein used in most medical therapies, says klas Wiman, a cancer cell biologist at the Karolinska Institute in Stockholm, Sweden. As a result, large pharmaceutical companies have shied away from this approach and progress is very slow, he said. “For large pharmaceutical companies, it is somewhat out of the mainstream.â€
However, its return will be huge. Not only does it be able to treat a variety of cancers strategically, but only a few drug classes are needed, especially when combined with chemotherapy drugs that induce tumor cell damage and prompt p53 to respond. P53 mutations tend to appear at the core of the protein, and this site determines the binding of the protein to DNA and has an important influence on its shape. "Cell" magazine articles and animal studies have shown that drugs that restore p53 activity can not only act on one of the mutations in the protein, but on a variety of genetic mutations, said Alan Fersht, a chemist at the University of Cambridge in the United Kingdom. “The beauty of these drugs is that they can be widely used.â€
Crazy research
An understanding of the mysterious power of p53 in suppressing tumors began after the protein was discovered in 1979. In the beginning, it was considered a tumor that allowed a cell to become cancerous under certain conditions. About 10 years later, it was confirmed to be able to bind to DNA and open up other gene expression designed to treat cell damage. If there are more cells in the cell that interact with p53, the damage is more extensive, and it triggers p53 to signal a cell suicide.
It is now known that this protein can control and interact with dozens of genes and proteins, which help regulate the molecular activity cycle of cell growth and replication. Because of its importance, its presence in cells is strictly controlled. Another protein, MDM2, entangles the p53 molecule and destroys them, thus controlling its number.
However, this control mechanism may fail for a variety of reasons. When p53 itself mutates, MDM2 can no longer attack it. Thus, the failed p53 protein accumulates in the cell in an uncontrolled state and allows the remaining healthy protein to continue to work. Without these “genomic guardiansâ€, pre-cancer cells will survive and multiply. This gives them the opportunity to accumulate the extra mutations they need to eventually become completely malignant tumors.
Most anti-cancer attempts to target p53 have sought to increase this protein level. One popular approach is to prevent MDM2 and its relative MDMX from reducing p53 levels. The hope is that doing so will allow some of the p53, which has not yet been genetically altered, to survive longer and kill harmful cells. “Everyone is frantically studying these (drugs),†said David Lane, a cancer biologist at the p53 co-discoverer and the New Family Skin Science, Technology and Research Bureau.
Targeting core
Currently, Fersht, Lane, Amaro and other researchers hope to focus on the core of the problem: mutation p53. In the 1990s, Lane and his colleagues conducted cancer cell test experiments, showing that some drugs can restore the normal function of mutant p53. But they don't always play the role that researchers think. The results showed that a drug called CP-31398 actually triggered cell death, but not by restoring p53. They kill them by disrupting the DNA of the cells.
Since then, the researchers have done a better job. For example, in 1998, the Wiman team tested the National Cancer Institute's 2000 series of drugs and found that two of them restored p53 activity and killed cancer cells. One of them, called MIRA-I, showed that it not only kills cancer cells, it is also toxic in mice. But another drug called PRIMA-1 has good prospects. Subsequent research has shown that it can be broken down into another compound called MQ. Three years ago, Amaro and colleagues reported that computer model results indicate that MQ is ligated into the sac formed inside the mutant p53 core. Her findings suggest that the drug supports the p53 protein to restore shape and save its function.
Currently, it is uncertain whether a p53 stabilization strategy can be successful, Lane said. But once it succeeds, it will far surpass other gene-targeted therapies, with a lasting effect on cancer treatment, benefiting millions of cancer patients every year. This rescue protein strategy will also pave the way for similar medical research aimed at restoring other variant proteins. This therapy has been helpful in combating vesicular fibrosis.
However, the primary goal of the long-term treatment of this therapy is to prevent tumors. Wiman emphasizes that current blood testing techniques have been able to reveal that individuals' cancer-associated proteins enter the bloodstream, even before they become fully grown tumors.
One day in the future, it may provide a p53-reducing drug to people with similar signs of cancer, causing their cell guards to spot signs of cancer and sweeping them away before they begin. "In the long run, this idea is very attractive," Lane said.
(A long-term dream in the field of cancer biology is to find a source of small molecule drugs that can restore p53 activity: Science)
It is large and soft, and it is difficult to track this molecular deformer with standard imaging tools. As a result, computational biologist Amaro of the University of California, San Diego switched to a supercomputer. She inserts a new X-ray snapshot of the p53 fragment and enhances the program to produce a video of each of the 1.6 million atoms of the protein at the microsecond (millionth of a second) level, so the continuity of the atomic level requires super The computer calculates about 1 month. She looks at the four copies of p53 that are connected to each other and then wrapped around a DNA strand. This is an important "dance" that p53 protein "jumps" before the message of cell self-destruction.
Amaro is not only interested in the behavior of healthy p53: she wants to understand the effects that p53 mutations may cause. In dozens of simulations, she and her colleagues tracked how ordinary p53 mutations further made this already soft-stable protein more unstable, distorting it and preventing it from binding to DNA. Some simulations have revealed additional content: or can provide support for a potential drug. Sometimes, the mutant protein core forms a small gap. When Amaro added virtual drug molecules to the model, the drug stayed in the crack, making p53 stable enough to return to normal function.
For Amaro and some other researchers, computer simulation has inspired. "A long-term dream in the field of cancer biology is to find small molecule drugs that can restore p53 activity," Amaro said. "We are very excited about this."
Great return
Conventional proteins are the most studied proteins in the scientific field and are also the focus of pharmaceutical companies. However, among the dozens of p53 drugs currently being developed, most drugs are only trying to improve the level of healthy p53. Although research in this area has been going on for decades, no drugs have yet entered the market.
Amaro's work demonstrates the progress that some scientific laboratories and small companies have used to target p53 in new ways: to save it after it gets sick. They are looking for drugs that bind to p53 and support the mutant p53 protein, allowing them to restore shape and function and perform routine tasks. One of these drugs has passed initial human safety testing, and a more advanced clinical trial is now underway in Europe. Other potential drugs are approaching human clinical trials. If clinically successful, they will significantly change the face of cancer treatment, in addition to other misfolded protein diseases, even Alzheimer's disease.
However, it won't be easy. Restoring the normal function of a variant protein is more difficult than the strategy of blocking only one protein used in most medical therapies, says klas Wiman, a cancer cell biologist at the Karolinska Institute in Stockholm, Sweden. As a result, large pharmaceutical companies have shied away from this approach and progress is very slow, he said. “For large pharmaceutical companies, it is somewhat out of the mainstream.â€
However, its return will be huge. Not only does it be able to treat a variety of cancers strategically, but only a few drug classes are needed, especially when combined with chemotherapy drugs that induce tumor cell damage and prompt p53 to respond. P53 mutations tend to appear at the core of the protein, and this site determines the binding of the protein to DNA and has an important influence on its shape. "Cell" magazine articles and animal studies have shown that drugs that restore p53 activity can not only act on one of the mutations in the protein, but on a variety of genetic mutations, said Alan Fersht, a chemist at the University of Cambridge in the United Kingdom. “The beauty of these drugs is that they can be widely used.â€
Crazy research
An understanding of the mysterious power of p53 in suppressing tumors began after the protein was discovered in 1979. In the beginning, it was considered a tumor that allowed a cell to become cancerous under certain conditions. About 10 years later, it was confirmed to be able to bind to DNA and open up other gene expression designed to treat cell damage. If there are more cells in the cell that interact with p53, the damage is more extensive, and it triggers p53 to signal a cell suicide.
It is now known that this protein can control and interact with dozens of genes and proteins, which help regulate the molecular activity cycle of cell growth and replication. Because of its importance, its presence in cells is strictly controlled. Another protein, MDM2, entangles the p53 molecule and destroys them, thus controlling its number.
However, this control mechanism may fail for a variety of reasons. When p53 itself mutates, MDM2 can no longer attack it. Thus, the failed p53 protein accumulates in the cell in an uncontrolled state and allows the remaining healthy protein to continue to work. Without these “genomic guardiansâ€, pre-cancer cells will survive and multiply. This gives them the opportunity to accumulate the extra mutations they need to eventually become completely malignant tumors.
Most anti-cancer attempts to target p53 have sought to increase this protein level. One popular approach is to prevent MDM2 and its relative MDMX from reducing p53 levels. The hope is that doing so will allow some of the p53, which has not yet been genetically altered, to survive longer and kill harmful cells. “Everyone is frantically studying these (drugs),†said David Lane, a cancer biologist at the p53 co-discoverer and the New Family Skin Science, Technology and Research Bureau.
Targeting core
Currently, Fersht, Lane, Amaro and other researchers hope to focus on the core of the problem: mutation p53. In the 1990s, Lane and his colleagues conducted cancer cell test experiments, showing that some drugs can restore the normal function of mutant p53. But they don't always play the role that researchers think. The results showed that a drug called CP-31398 actually triggered cell death, but not by restoring p53. They kill them by disrupting the DNA of the cells.
Since then, the researchers have done a better job. For example, in 1998, the Wiman team tested the National Cancer Institute's 2000 series of drugs and found that two of them restored p53 activity and killed cancer cells. One of them, called MIRA-I, showed that it not only kills cancer cells, it is also toxic in mice. But another drug called PRIMA-1 has good prospects. Subsequent research has shown that it can be broken down into another compound called MQ. Three years ago, Amaro and colleagues reported that computer model results indicate that MQ is ligated into the sac formed inside the mutant p53 core. Her findings suggest that the drug supports the p53 protein to restore shape and save its function.
Currently, it is uncertain whether a p53 stabilization strategy can be successful, Lane said. But once it succeeds, it will far surpass other gene-targeted therapies, with a lasting effect on cancer treatment, benefiting millions of cancer patients every year. This rescue protein strategy will also pave the way for similar medical research aimed at restoring other variant proteins. This therapy has been helpful in combating vesicular fibrosis.
However, the primary goal of the long-term treatment of this therapy is to prevent tumors. Wiman emphasizes that current blood testing techniques have been able to reveal that individuals' cancer-associated proteins enter the bloodstream, even before they become fully grown tumors.
One day in the future, it may provide a p53-reducing drug to people with similar signs of cancer, causing their cell guards to spot signs of cancer and sweeping them away before they begin. "In the long run, this idea is very attractive," Lane said.
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