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A newly discovered mechanism has paved the way for the next generation of proteasome inhibitors, according to a paper published in Chemistry & Biology.
Investigators developed a series of molecules that employ this mechanism, inhibiting the proteasome in 2 ways.
They are now planning to synthesize related compounds that may offer improved proteasome inhibition, target cancer cells more selectivity, and eliminate the resistance problems that occur with current drugs.
The group’s research began with epoxyketone, a molecule isolated from a cyanobacterium called carmaphycin, whose reactive group is the same as that of the proteasome inhibitor carfilzomib.
“Epoxyketones are very potent, selective inhibitors of the proteasome because they interact with this enzyme in 2 stages—the first reversible, and the second irreversible,” noted study author Daniela Trivella, PhD, of the Brazilian Biosciences National Laboratory at the Brazilian Center for Research in Energy and Materials in Campinas.
To optimize epoxyketone’s effects and find new reactive groups, the investigators developed and tested a series of synthetic analogs with slight structural modifications.
One of the molecules had an enone as a reactive group and had characteristics of carmaphycin and another natural molecule called syringolin, which was isolated from plant pathogens.
By investigating the reaction mechanisms of the new molecule, called carmaphycin-syringolin enone, the team verified that the enone interacts with the proteasome in 2 stages, with the second stage being irreversible.
The investigators also observed that, in the case of the enone, the second reaction occurs more slowly, increasing the duration of the reversible phase of carmaphycin-syringolin enone inhibition.
“Because the irreversible inactivation of the proteasome has toxic effects, the best window of reversibility observed for the carmaphycin-syringolin enone will potentially reduce the toxicity of this new class of proteasome inhibitors,” Dr Trivella said. “The compound would therefore present a balance between selectivity and potency.”
Toxicity tests are still underway. But the investigators have already conducted studies to determine exactly how the interaction between the enzyme target and the carmaphycin-syringolin enone target occurs.
“We discovered that a chemical reaction called hydroamination occurs, which had never before [been] seen under physiological conditions,” Dr Trivella said.
“This type of reaction is frequently used by synthetic chemists in preparing substances, but, normally, it requires very specific temperature and pH conditions and the use of catalysts to occur. It has never been reported as a mechanism of enzyme inhibition.”
Inspired by this new mechanism for proteasome inhibition, the investigators plan to synthesize and test a new series of carmaphycin-syringolin enone analogs to determine their effects on the therapeutic window and assess whether they are also capable of reacting with proteasomes that are resistant to traditional inhibitors.
