Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia

Zhifu Xie; Mei Zhang; Qian Song; Long Cheng; Xinwen Zhang; Gaolei Song; Xinyu Sun; Min Gu; Chendong Zhou; Yangming Zhang; Kexin Zhu; Jianpeng Yin; Xiaoyan Chen; Jingya Li; Fajun Nan

doi:10.1016/j.apsb.2022.06.011

Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia

Acta Pharm Sin B. 2023 Feb;13(2):739-753. doi: 10.1016/j.apsb.2022.06.011. Epub 2022 Jun 18.

Authors

Zhifu Xie¹, Mei Zhang¹, Qian Song^{1

2}, Long Cheng^{1

2}, Xinwen Zhang¹, Gaolei Song^{1

2}, Xinyu Sun¹, Min Gu¹, Chendong Zhou¹, Yangming Zhang^{1

3}, Kexin Zhu¹, Jianpeng Yin⁴, Xiaoyan Chen¹, Jingya Li^{1

2}, Fajun Nan^{1

2

4}

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² University of Chinese Academy of Sciences, Beijing 100049, China.
³ Burgeon Therapeutics Co., Ltd., Shanghai 201203, China.
⁴ Drug Discovery Shandong Laboratory, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.

Abstract

Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis. In this study, we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC₅₀ = 5.31 ± 1.2 μmol/L in vitro. 326E treatment reduced de novo lipogenesis, and increased cholesterol efflux in vitro and in vivo. 326E was rapidly absorbed after oral administration, exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE^-/- mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.

Keywords: ACLY inhibitor; ATP-Citrate lyase (ACLY); Atherosclerosis; Cholesterol efflux; Hypercholesterolemia; Lipogenesis; Liver.