Targeting a single enzyme that diverts the respiratory cycle in activated macrophages could offer new hope for treating inflammatory conditions, such as arthritis, sepsis, and autoimmune diseases. Scientists at the U.K.’s Imperial College Faculty of Medicine and Queen Mary University of London (QMUL) and Ergon Pharmaceuticals in the U.S. have shown that a drug in preclinical development by Ergon effectively reduces inflammation in rodent models of rheumatoid arthritis and severe kidney inflammation by decreasing macrophage infiltration.
The therapeutic concept is founded on the discovery that when macrophages are activated by exposure to microbial antigens their metabolism is diverted from its normal path to generate antimicrobial compounds. This diversion, mediated by the enzyme branched chain aminotransferase 1 (BCAT1), effectively disrupts the tricarboxylic acid cycle (TCA). BCAT1 is involved in breaking down branched-chain amino acids, such as leucine, to generate macromolecule precursors.
“All indications point toward a completely novel pathway that is linked to the newly discovered broken TCA cycle,” suggested Jacques Behmoaras, Ph.D., at Imperial College, and Ergon’s founder and director of R&D, Dr. Adonia Papathanassiu, who co-led the research. Speaking to GEN, they said, “This is very exciting for us as it provides the opportunity for the development of BCAT1 inhibitors as standalone anti-inflammatory therapies for patients that do not respond well to current treatments or in combination with other drugs for patients with partial responses to common therapies.”
The teams at Imperial College and at Ergon had independently identified BCAT1 in macrophages as an important and druggable target in inflammation. Working together with the team at QMUL, headed by Claudio Mauro, Ph.D., the researchers showed that blocking BCAT1 using Ergon’s small-molecule leucine analog ERG240 prevented BCAT1 from diverting the cells’ metabolism. In the mouse collagen-induced arthritis model, treatment using ERG240 reduced joint inflammation by more than 50% and protected joint integrity. In the rat crescentic glomerulonephritis model, ERG240 therapy improved kidney function by reducing macrophage infiltration into affected tissues.
“Thus, macrophage BCAT1 and its ability to interfere with metabolic reprogramming is an attractive pharmacological target for the treatment of chronic inflammatory diseases,” the researchers conclude in their published paper in Nature Communications, which is titled “BCAT1 Controls Metabolic Reprogramming in Activated Human Macrophages and Is Associated with Inflammatory Diseases.”
Having independently identified BCAT1 as a key, druggable target in inflammation, the Imperial and Ergon teams recognized that they brought different sets of skills to the research, Drs. Papthanassiu, Mauro, and Behmoaras explained to GEN. These include “a systems biology approach that allows the unmasking of new cellular pathways (Imperial) and the pharmacological inhibition of BCAT1 that allows proof-of-principle experimentation in disease models (Ergon).”
“BCAT1 was identified by the Imperial team as the hub of a macrophage gene network important in inflammation in a previous article published in Cell Reports,” Dr. Behmoaras added. “It suggested that leucine metabolism could be an important pathway in the activation of these cells. Ergon was exploring the role of BCAT1 in cancer when it became evident that the protein controls the expression of cytokines that are important in inflammation.”
Working together to uncover the role of BCAT1 in inflammation was the next logical step, the researchers point out. “The two teams were then partnered with the QMUL team, which brought in expertise in the metabolic regulation of inflammatory responses, in order to uncover how an enzyme (BCAT1) responsible for initiating the catabolism of branched-chain amino acids, controls the expression of inflammatory cytokines. The Imperial–QMUL–Ergon collaboration was essential for testing a potential drug target in vitro in primary human cells and in vivo in disease models.”
“The team at QMUL provided expertise for the measurement of cell metabolism in real time,” Dr. Behmoaras stressed. “This was pivotal to link the effect of BCAT1 inhibition to cell metabolism.”
ERG240 is currently in preclinical development by Ergon for the potential treatment of autoimmune diseases, such as rheumatoid arthritis, Dr. Papathanassiu explained to GEN. The company is, in addition, working on second-generation BCAT1 inhibitors that are structurally related to ERG24.
“We are looking forward to continue our work on BCAT1,” commented Drs. Papathanassiu and Behmoaras. “We have actually expanded our collaboration network to include Dr. Christian Frezza’s lab at Cambridge University, where we are exploring the effect of the pharmacological inhibition of BCAT1 on TCA metabolites. The objective of our collaborative research on BCAT1 is to uncover upstream and downstream proteins participating in the BCAT1 pathway. We are also looking beyond BCAT1, and we are hoping to create a long-term collaboration to develop drugs for macrophage-driven diseases based on targets identified through a systems biology methodology. As with all anti-inflammatory therapies, the challenge with the long-term drugging of BCAT1 will be to reduce unwanted inflammation without hampering the ability of the body to respond to microbial invaders.”
Ergon is a preclinical-stage company focused on identifying drug candidates for unmet needs, based on novel targets, Dr. Papathanassiu noted. One of the firm’s near-future goals is to outlicense ERG240, GEN was informed. “As such, we are actively looking to partner the development of our drug candidates with companies that have clinical expertise.”