Scientists have developed a substance that inhibits the proteins of the group BET and suppresses the development of cancer of various types more efficiently than analogs that are clinical trials. The drug not only directly inhibits the growth of cancer cells, but does not give the recruit associated with tumor macrophages. The researchers found the molecular mechanism of the effect of BET inhibitors on this interaction. Article published in the journal Nature Communications.
Epigenetic interactions play an important role in the development of various types of cancer, which is why many therapies aimed at suppression of these mechanisms. In particular, violations in the work of the group BET proteins are associated with cancer. These molecules recognize atsetilirovannye histones, sit on them and participate in the regulation of DNA transcription. Especially a lot of BET proteins in the super-enhancers, which trigger the production of factors important for the development of cancer.
There are a number of BET inhibitors, in particular, protein BRD4, which is effective against cancer in animal models. However, in clinical trials the efficacy of the drugs was not so high. Researchers are trying to improve matter, but has not yet managed to develop a drug that would be effective and available for oral administration.
Other targeted therapies of cancer — related tumor macrophages, immune cells that are found in large number find in the tumor tissues. When injected into the tumor these cells are rebuilt and help the cancer cells to develop, trigger the growth of blood vessels and suppress the immune system.
A group of scientists from China and the United States under the leadership of Qin Yang (Qin Yan) from Yale school of medicine have modified one of the well proved themselves in clinical trials an inhibitor of BRD4 and increased its efficiency. The best of the received instances turned out to be a substance called NHWD-870. Its action was tested on cell cultures of various types of tumors.
Then studied the pharmacokinetics of a drug when oral administration to mice and rats. The drug is also tested on mouse models nine different cancer, including lung, ovarian and breast cancer, lymphoma and melanoma.
NHWD-870 turned out to be 3 times more effective than its predecessor, and 50 times — than JQ1, a standard inhibitor of BET. He suppressed the expression of BRD4 and proto-oncogene c-MYC in the culture of tumor cells, leading to their death.