Cryo-EM points to new cancer target

Editorial

Rebecca Pool

Friday, April 5, 2019 - 14:15
Image: 3D structure of metabolic enzyme ATP-citrate lyase. [Liang Tong, Columbia University; Nimbus; Nature]
 
US-based researchers have determined the structure of a metabolic enzyme that plays a key role in cancer cell proliferation and other cellular processes.
 
Using cryo-EM, researchers from Columbia University and Nimbus Therapeutics determined the 3D structure of human ATP-citrate lyase (ACLY), which could now be the next major molecular target in cancer treatment.
 
While previous experiments have resolved fragments of the enzyme, the current work reveals the full structure of human ACLY at high resolution.
 
“ACLY is a metabolic enzyme that controls many processes in the cell, including fatty acid synthesis in cancer cells. By inhibiting this enzyme, hopefully we can control cancer growth,” says Professor Liang Tong from Biological Sciences at Columbia. “In addition, the enzyme has other roles, including cholesterol biosynthesis, so inhibitors against this enzyme could also be useful toward controlling cholesterol levels.”
 
Targeted therapy is an active area of cancer research that involves identifying specific molecules in cancer cells that help them grow, divide and spread.
 
By targeting these changes or blocking their effects with therapeutic drugs, this type of treatment interferes with the progression of cancer cells.
 
Earlier this year, another group of researchers presented results of a phase 3 clinical trial for bempedoic acid, an oral therapy for the treatment of patients with high cholesterol.
 
The drug, a first-generation ACLY inhibitor, was shown to reduce low-density lipoprotein (LDL) cholesterol by 30 percent when taken alone and an additional 20 percent in combination with statins.
 
ACLY has been found to be over-expressed in several types of cancers and experiments have found that “turning off” ACLY leads cancer cells to stop growing and dividing.
 
Knowledge of the complex molecular architecture of ACLY will point to the best areas to focus on for inhibition, paving the way for targeted drug development.
 
The cryo-EM results revealed an unexpected mechanism for effective inhibition of ACLY with the researchers finding that a significant change in the enzyme's structure is needed for the inhibitor to bind.
 
This structural change then indirectly blocks a substrate from binding to ACLY, preventing enzyme activity from occurring as it should.
 
This novel mechanism of ACLY inhibition could provide a better approach for developing drugs to treat cancer and metabolic disorders.
 
Research is published in Nature.
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