A research team from Columbia University and Nimbus Therapeutics has successfully determined the 3D structure of human ATP-citrate lyase (ACLY), a metabolic enzyme that plays a key role in cancer cell proliferation and other cellular processes.
Previous experiments have included fragments of the enzyme, but the current work reveals the full structure of human ACLY at high resolution. Such findings, according to the team, represent the first step in better understanding the enzyme in order to create effective molecular targeted therapies for patients.
“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 Liang Tong, professor and department chair of 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 helps them grow, divide and spread. By targeting these changes or blocking the 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.
Tong and Jia Wei, an associate research scientist in his lab, used cryogenic electron microscopy (cryo-EM) to resolve the complex structure of ACLY, using a facility at the New York Structural Biology Center. Cryo-EM allows for high-resolution imaging of frozen biological specimens with an electron microscope. A series of 2D images are then computationally reconstructed into accurate, detailed 3D models of intricate biological structures like proteins, viruses and cells.
“A critical part of the drug discovery process is to understand how the compounds work at the molecular level,” says Tong, whose lab specializes in the mechanism and function of biological molecules. “This means determining the structure of the compound bound to the target, which in this case is ACLY.”
The cryo-EM results revealed an unexpected mechanism for effective inhibition of ACLY. The team found 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.
“This is a terrific example of how our work at Nimbus combines cutting-edge technology, computational approaches and deep drug discovery experience to generate new scientific insights,” says Jeb Keiper, chief executive officer at Nimbus. “We’re excited to continue collaborating with experts as we interrogate new targets and deepen our pipeline of therapies.”