Targeting ACSS2 with a Transition-State Mimetic Inhibits Triple-Negative Breast Cancer Growth

Abstract

Acetyl-CoA is a vitally important and versatile metabolite used for many cellular processes including fatty acid synthesis, ATP production, and protein acetylation. Recent studies have shown that cancer cells upregulate acetyl-CoA synthetase 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in response to stresses such as low nutrient availability and hypoxia. Stressed cancer cells use ACSS2 as a means to exploit acetate as an alternative nutrient source. Genetic depletion of ACSS2 in tumors inhibits the growth of a wide variety of cancers. However, there are no studies on the use of an ACSS2 inhibitor to block tumor growth. In this study, we synthesized a small-molecule inhibitor that acts as a transition-state mimetic to block ACSS2 activity in vitro and in vivo. Pharmacologic inhibition of ACSS2 as a single agent impaired breast tumor growth. Collectively, our findings suggest that targeting ACSS2 may be an effective therapeutic approach for the treatment of patients with breast cancer. Significance: These findings suggest that targeting acetate metabolism through ACSS2 inhibitors has the potential to safely and effectively treat a wide range of patients with cancer.

Targeting cancer metabolism in the era of precision oncology

“…152 ) is also induced by hypoxia and low serum cell culture media and maintains cancer cell growth under stress. Inhibition of ACSS2 by inducible shRNAs 152 or CRISPR knockout 153,154 suppressed in vivo tumorigenesis. These studies collectively indicate that ACSS2 inhibition could have beneficial antitumour effects.…”

“…As such, ACSS2 inhibitors are being developed 155 (patents WO/2019/097515, WO/2015/175845 and WO/2020/252407) and await testing in tumour models. A predicted transition-state mimetic inhibitor, VY-3-135, was recently documented to have nanomolar biological activity in vitro and has efficacy in xenograft mouse models with high ACSS2 expression but not in those with low expression 153 . Further, VY-3-135 inhibits the labelling of palmitate by D 3 -acetate, providing evidence for in vivo target engagement.…”

The Uniqueness of Clear Cell Renal Cell Carcinoma: Summary of the Process and Abnormality of Glucose Metabolism and Lipid Metabolism in ccRCC

“…Nonetheless, a study on the relationship between ACSS2 and cancer has shown that ACSS2 -mediated histone acetylation plays an important role in maintaining cell homeostasis and tumor development, providing a clearer path for the research of ACSS2 ( 84 ). It is also a new idea to explore the therapy of ccRCC and other cancers that target this gene ( 85 , 86 ). Based on the above study on the application value of ACLY and ACSS2 in cancer treatment, we believe that it is highly practical to develop new treatment methods based on these two genes.…”

Structural Characterization of the Reaction and Substrate Specificity Mechanisms of Pathogenic Fungal Acetyl-CoA Synthetases

“…Recently, Miller et al reported that this inhibitor inhibited ACSS2 at less than 50% at the highest drug concentrations, suggesting that it is not a particularly effective inhibitor of ACS. 34 Thus, small differences in affinity between the two enzymes for the inhibitor may be amplified. Since ACSS2 does not appear essential in mammals, 4 , 5 high specificity for fungal enzymes, however, is not likely to be as important as potent on-target activity in the development of antifungal ACS inhibitors.…”