New advances in anti-cancer compounds! Cell 'lava lamp' effect makes cancer drugs more effective

Pharmacometabolic kinetics refers to the invivial process of a drug, studying the absorption, distribution, metabolism and excretion of drugs, as well as the laws of blood concentration over timeIt is widely believed that the drug will spread evenly within the cell, so for cancer cells, the anti-cancer compound will be concentrated in the cancer cellspreciseposition?A long-standing assumption in the pharmaceutical industry that drug molecules spread evenly when they enter cells, but biologist Rick Young says, "It's a far cry from the truth." In a study published June 18 in the journal Nature,Yang and his colleagues at the Whitehead Institute in Cambridge, Massachusetts, said anti-cancer compounds are concentrated in the precise location of cells because of a phenomenon called phase separation, in which all cells separate their contentsThese results challenge the basic assumptions of the role, dynamics and distribution of small molecule therapiesResearchers have led new strategies to combat the design of new coronavirus drugs and may help explain why so many of the treatments that work in the lab ultimately fail to treat humans"This paper has the opportunity to reshape our understanding of drug metabolism and drug-targeted cells," said Jonathan Ditlev, a cell biophysicist at the children'
sHospital in Toronto, Canada,"
biological materials have an easy way to establish order inside cells, like small droplets in lava lamps or oilthat shaken in water, proteins, DNA and other cellular components can self-organize liquid droplets called condensate, helping to separate cellsresearchers have previously shown that this effect occurs in natural molecules, but recent studies have shown that synthetic compounds can selectively isolate in droplets in a similar wayThis phenomenon can be used to enable certain drugs to hit targets more effectively, while limiting the unintended toxicity that causes harmful side effects "If we can start to understand how these condensates distinguish between small molecules, we can develop existing condensate methods so that we can better treat diseases," said Ditlev, In the study, cluster of cisplatin Yang and his team tracked the dynamics of five small molecule cancer drugs in condensate, test tube experiments and cultured human cancer cells They began using cisplatin, the basis of many chemotherapy regimens By mixing cisplatin with known condensed proteins in the nucleus, the researchers found that cisplatin selectively gathers in droplets formed by a gene-activated protein called MED1 where MED1 is found, cisplatin molecules come together: the concentration of the drug inside the condensate is 600 times higher than the outside The researchers found that MED1 primarily acts on cancer-promoting genes, so cisplatin eventually targets the same DNA with its toxic platinum atoms -- essentially attacking the most painful parts of cancer cells effects also seem to affect drug resistance The team found that breast cancer drug tamoxifen also clots in MED1 clots But the levels of MED1 produced by cancer cells that are resistant to moxifen are much higher, and the team found that this caused the concentrate to expand, dilute the drug and impair its effectiveness "Every cancer drug we've examined finds itself concentrated in these separate coagulants, and I don't know of any case where that can be ignored, " says yang, of the team is now trying to figure out why the drug molecules enter the condensation state "If we can learn more about the "grammar" of molecules, then we may be able to modify small molecules to focus them in the right place," said Isaac Klein, an oncologist at the Whitehead Institute and co-author of the study "
coronavirus condensate Klein and co-author ann Boija, a molecular biologist at the Whitehead Institute, have sat on the past two months to combat SARS-CoV-2, a coronavirus that causes COVID-19 in unpublished experiments, they found that three key viral proteins associated with the SARS-CoV-2 replication mechanism came together to form a condensed state that absorbs and concentrates drug compounds "This is the result of the screening we need to start screening to see if small molecules have the ability to inhibit the replication of viral RNA and selectively split into concentrates where replication occurs, " said Yang "In a rigorous trial, the only antiviral drug that has been shown to be effective on COVID-19 is a molecule called Redsewe, which offers only limited benefits, which Yang suspects may be due to poor separation of the drug Boston-based Dewpoint Therapeutics chief scientific officer Mark Murcko says that from now on, separation will be part of drug development The company's goal is to develop drugs in the biology of condensation by destroying disease-related condensations, or by accumulating specific condensations in cells but not everyone believes it Robert Tjian, a biochemist at the University of California, Berkeley, believes that while there are other mechanisms that explain how natural and synthetic molecules accumulate in cells, scientists are eager to link condensation to a variety of biological processes He worries that the excitement generated by a paper like Yang's could trigger research into drugs designed to enter phase-separation droplets that may only exist in the lab Lauren Source: