A Promising Metabolic Enzyme as a Cancer Treatment Target

Scientists from Columbia University, in collaboration with researchers at Nimbus Therapeutics, have demystified a metabolic enzyme that could be the next major molecular target in cancer treatment.

The team determined for the first time the 3D structure of human ATP-citrate lyase (ACLY) – which plays a key role in the proliferation of cancer cells and other cellular processes -.

The results, published on April 3 in Nature, represent a first step towards a better understanding of the enzyme in order to create effective molecular therapies for patients.

While previous experiments have been successful with fragments of the enzyme, current work reveals the complete structure of human ACLY at high resolution.

"ACLY is a metabolic enzyme that controls many cellular processes, including the synthesis of fatty acids in cancer cells, and by inhibiting this enzyme we hope to be able to control the growth of cancer," said Professor Liang Tong, Ph.D. William R. Kenan Jr. Biological Sciences Chair at Columbia and lead author of the study. "In addition, the enzyme has other roles, including cholesterol biosynthesis, so inhibitors of this enzyme could also be useful for controlling cholesterol levels."

Targeted Therapy is an active area of ​​cancer research that involves identifying specific molecules in cancer cells to help them grow, divide and spread. By targeting these modifications 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 the results of a phase 3 clinical trial of bempedoic acid, an oral therapy for the treatment of patients with high cholesterol levels. The drug, a first-generation inhibitor of ACLY, has been shown to reduce LDL cholesterol by 30% when it was taken alone and by an additional 20% in combination with lipoprotein (LDL). statins.

ACLY has been found to be overexpressed in many types of cancers and experiments have shown that turning them off means that the cancer cells stop growing and dividing. The knowledge of the complex molecular architecture of ACLY will show you the best areas of inhibition, paving the way for targeted drug development.

Tong and Jia Wei, badociate researcher in his lab, applied an imaging technique known as cryogenic electron microscopy (cryo-EM) in order to solve the complex structure of ACLY, at the same time. badistance from the New York Center for Structural Biology. Cryo-EM allows high resolution imaging of frozen biological samples under the electron microscope. A series of two-dimensional images is then computationally reconstructed into accurate and detailed 3D models of complex biological structures such as proteins, viruses, and cells.

"An essential part of the drug discovery process is understanding how compounds work at the molecular level," said Tong, whose lab specializes in the mechanism and function of biological molecules. "It means to determine the structure of the compound bound to the target, which in this case is ACLY."

The results of cryo-EM revealed an unexpected mechanism of effective inhibition of ACLY. The team discovered that a significant change in the structure of the enzyme is necessary for the inhibitor to bind. This structural change then indirectly prevents a substrate from binding to ACLY, thereby preventing enzymatic activity. This new mechanism of ACLY inhibition could be a better approach for the development of drugs to treat cancer and metabolic disorders.

"This article is a great example of how our work at Nimbus combines cutting-edge technology, IT approaches and deep drug discovery experience to generate new scientific knowledge," said Jeb Keiper, President and CEO of Nimbus. . "We are pleased to continue to collaborate with experts to interrogate new targets and deepen our portfolio of therapies."

This article has been republished from documents provided by Columbia University. Note: Content may have changed for length and content. For more information, please contact the cited source.

Reference: Wei et al. 2019. Allosteric mechanism for a potent inhibition of human ATP-citrate lyase. Nature. DOI: https: //doi.org/10.1038/s41586-019-1094-6.