"Phase separation" phenomenon makes anticancer drugs more effective

fluorescently labeled anti-cancer drug cisplatin molecules gather in cell droplets. Photo Source: Isaac Klein/Whitehead Institute
The pharmaceutical industry has long assumed that drug molecules are evenly distributed when they enter cells, but biologist Rick Young says this is "a far from the truth." In a recent study published in Science, Young and colleagues at the Whitehead Institute in Cambridge, Massachusetts, found that cancer drug compounds are concentrated precisely in cells because of a phenomenon called phase separation, through which all cells separate their components.
results challenge basic assumptions about the role, dynamics and distribution of small molecule therapy drugs. They have provided new strategies for drug design to combat the new coronavirus and may help explain why so many effective treatments in laboratory dishes ultimately fail to treat humans.
biological materials have an easy way to establish order within cells. Like spots in lava lamps or oil that shakes in water, proteins, RNA, and other cell components can self-organize into droplets called condensates, which help separate the inside of cells.
researchers have previously shown that this effect occurs in natural molecules, but new research suggests that synthetic compounds can be selectively isolated in droplets in a similar way. This phenomenon can be used to make certain drugs more effective in achieving their objectives, while limiting the unintended toxicity that leads to harmful side effects.
study, Young and his team tracked the dynamics of five small molecule anticancer drugs in cohesion, test tube trials and cultured human cancer cells. They start with the basic drug cisplatin in many chemotherapy programs. By mixing cisplatin with proteins known to form coagulants in the nuclei of cells, the researchers found that cisplatin selectively congregates in droplets formed by a gene-activated protein called MED1.
, said: "Every cancer drug we studied was concentrated in these isolated condensed substances. "
team is currently trying to figure out why the drug molecules entered the polymer." If we can learn more about the 'grammar' of molecules, then it is possible to modify small molecules to concentrate them in the right place," said Study co-author Isaac Klein, an oncologist at the Whitehead Institute.
Klein and co-collaborator Ann Boija, molecular biologists at the Whitehead Institute, have spent the past two months applying their experience to the fight against the new coronavirus.
unsealed experiments, they found that three key viral proteins associated with the new coronavirus replication mechanism came together in the form of condensed bodies that could absorb and concentrate pharmaceutical compounds.
phase separation "will be part of the drug discovery from now on," said Mark Murcko, chief scientist at Dewpoint Therapeutics in Boston.
but not everyone believes it. Robert Tjian, a biochemist at the University of California, Berkeley, says scientists are eager to link condensation to a variety of biological processes, although other mechanisms could explain how natural and synthetic molecules accumulate in cells. He worries that the excitement caused by papers like Young could trigger a study of drugs designed to enter phase-separated droplets, which will be designed to enter phase-separating droplets that may only exist in the lab.
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