TAMPA, Fla. July 24: Researchers at Moffitt Cancer Center have developed a new chemical approach that could help make targeted cancer medicines safer and more precise. The discovery gives scientists a new way to design drugs that bind more selectively to cancer-driving proteins while reducing unwanted interactions that can lead to side effects.
The findings, published in Science, could help improve a wide range of targeted cancer therapies and eventually medicines for other diseases.
Covalent inhibitors are among the most powerful targeted cancer drugs because they permanently attach to disease-driving proteins, keeping them switched off longer than traditional medicines. More than a dozen covalent drugs have already been approved to treat cancer.
However, the same chemical groups that allow these drugs to bind to cancer proteins can also react with healthy proteins. Those unintended interactions have been linked to side effects and have limited how broadly this type of drug can be used.
To address that challenge, a team led by Justin M. Lopchuk, Ph.D., associate member in Moffitt’s Drug Discovery Department, developed a new type of chemical “warhead” built around a small, highly strained molecular structure called a bicyclobutane. The new design strongly prefers binding to cysteine, the amino acid targeted by most approved covalent cancer drugs, while avoiding many of the unwanted reactions seen with existing chemistries.
The researchers also developed a simple way to add the new chemistry to drug candidates late in development. Instead of designing an entirely new drug, scientists can replace the older chemical group on medicines that are already well understood, making it easier to create improved versions of existing therapies.
To test the approach, the team redesigned several experimental and approved cancer drugs, including dacomitinib, an FDA-approved treatment for certain lung cancers. The modified version maintained its ability to block its intended cancer target while interacting with far fewer unintended proteins.
The researchers then tested the redesigned drug in mice with human lung tumors. It reduced tumor growth as effectively as the approved medicine while showing improved drug exposure in the body and no obvious signs of toxicity during the study.
“Covalent drugs are powerful, but their reactivity has always cut both ways,” Lopchuk said. “We wanted a warhead that only reacts where it’s supposed to. That gave us much cleaner compounds without sacrificing potency.”
Researchers warn that additional studies are needed before the technology can be tested in patients. However, because the chemistry can be incorporated into existing drug candidates, they believe it could provide a practical way to improve many targeted medicines without starting the drug discovery process from scratch.
“Because we can install these groups so late in the process, the approach could give drug developers a new, practical way to design safer targeted therapies without giving up the effectiveness patients need,” Lopchuk said.
This study was supported by the National Institutes of Health (R35-GM142577, P30-CA076292), the Moffitt Cancer Center Lung Cancer Center of Excellence, a Moffitt Team Science Award and the Moffitt Foundation.
