Defining RNA–Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor of an Oncogenic Noncoding RNA
TSRI Scientists have designed 2 new drug candidates to target prostate and triple negative breast cancers. The new research, published recently as 2 separate studies in ACS Central Science and Journal of the American Chemical Society, demonstrates that a new class of drugs, small molecule RNA inhibitors can target and kill specific types of cancer. RNA defects can lead to cancers, ALS, myotonic dystrophy and many other diseases. In their ACS Central Science study, Prof. Disney and his colleagues used DNA sequencing to evaluate thousands of small molecules as potential drug candidates. The researchers were on the lookout for molecules that could bind precisely with defective RNAs – like keys fitting in the right locks.
This strategy led them to a compound that targets the precursor molecule to an RNA called microRNA-18a. This RNA had caught the attention of scientists who found that mature microRNA-18a inhibits a protein that suppresses cancer. When microRNA-18a is overexpressed, cancers just keep growing. Disney and his team tested their compound, Targapremir-18a, and found it could target microRNA-18a and trigger prostate cancer cell death.
Disney said the precise binding of Targapremir-18a to microRNA-18a means a cancer drug that follows this strategy would be likely to kill prostate cancer cells without causing the broader side effects seen with many other cancer therapies. And there may be even bigger implications. “We could apply the strategy used in this study to quickly identify and design small molecule drugs for other RNA-associated diseases,” explained Sai Velagapudi, a research associate in the Disney lab.
The same screening strategy led the researchers to a drug candidate to target triple negative breast cancer. Triple negative breast cancer is especially hard to treat because it lacks the receptors, such as the estrogen receptor, targeted with other cancer drugs. The Disney lab aimed to get around this problem by instead targeting an RNA called microRNA-210, which is overexpressed in solid breast cancer tumors.
The researchers tested Targapremir-210, in mouse models of triple negative breast cancer and it significantly slowed down tumor growth. In fact, a single dose decreased tumor size by 60% over a 3-week period. The researchers analyzed these smaller tumors and discovered that they also expressed less microRNA-210 compared with untreated tumors. Targapremir-210 appears to work by reversing a circuit that tells cells to “survive at all costs” and become cancerous. With microRNA-210 in check, cells regain their normal function and cancer cannot grow.
“We believe Targapremir-210 can provide a potentially more precise, targeted therapy that would not harm healthy cells,” said TSRI Graduate Student Matthew G. Costales. Next, the researchers plan to further develop their molecule-screening strategy into a platform to test molecules against any form of RNA defect-related disease. http://www.scripps.edu/news/press/2017/20170309disney.html
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