Scientists at The Scripps Research Institute (TSRI) in La Jolla, California, are looking for ways to disrupt the function of MYC, a regulator of cancer; which until now, it was believed not pharmaceutically treatable. In fact, it seems that they have achieved their goal, as they have discovered a molecule that is able to move and disrupt critical interactions between MYC and its binding partner.
The research, published the week of August 11 in the journal Proceedings of the National Academy of Sciences, also shows the drug candidate can stop tumor growth in animal models.
MYC is a transcriptional factor, meaning it controls gene expression. When MYC is overexpressed or amplified, the unregulated expression of genes involved in cell proliferation follows; which is a key step in cancer growth. MYC is involved in a majority of cancers and for years has challenged researchers who sought to disrupt its activity in cancer cells.
Usually when it comes to designing a drug, the structure of a disease-related molecule is determined. Then weak points are found to attack and interfere with the molecule function. However, the researches pointed out that MYC is different.
MYC is different, explain Jonathan Ross Hart, study coauthor and scientists at the Vogt laboratory at TSRI, “At room temperature or body temperature, MYC without any binding partners is random and constantly shifting,” and added that “It’s like a piece of spaghetti.”
So instead of specially designing a compound to target the structure of MYC, the researchers tested a range of compounds from a library developed by Kim Janda, study coauthor. He terms these compounds “credit cards”, referencing to the trick any cat burglar knows: to open a locked door, slide a credit card past the latch. Precisely, the idea is to see if one of these compounds acts as the credit card, disrupting the interactions between MYC and other proteins important in cell proliferation.
Finally one did, a small molecule called KJ-Pyr-9.
To further investigate, the researchers ran additional tests using cell lines and rodent models. The team found that cells that depend on MYC die if treated with KJ-Pyr-9. In fact, a dose of KJ-Pyr-9 made it seem as if MYC was not there at all. In addition, when mice with MYC-dependent tumors received KJ-Pyr-9, the tumors showed no growth after 31 days, compared with significant tumor growth in untreated mice.
“We finally hit a home run with this—maybe a grand slam,” said Kim Janda; who hopes further research will reveal exactly how KJ-Pyr-9 interacts with MYC and how the compound can more effectively reach tumor cells.
Via: Scripps Research Institute
