Opportunities and Challenges for Inhibitors Targeting Citrate Transport and Metabolism in Drug Discovery

Abstract

Lipid metabolism disorder is closely related to metabolic diseases, inflammation, and cancer. The concentration of citrate in the cytosol has a significant impact on lipid synthesis. The expression of citrate transporters (SLC13A5 and SLC25A1) and metabolic enzymes (ACLY) proves to be substantially raised in various diseases related to disorders of lipid metabolism, such as hyperlipemia, nonalcoholic fatty liver disease, and prostate cancer. Targeting key proteins in the citrate transport and metabolic pathways is considered an effective strategy for treating various metabolic diseases. However, there is currently only one ACLY inhibitor approved for marketing, and no SLC13A5 inhibitor has entered clinical research. Further development of drugs targeting citrate transport and metabolism is needed for the treatment of metabolic diseases. This perspective summarizes the biological role, therapeutic potential, and research progress of citrate transport and metabolism and then discusses the achievements and prospects of modulators targeting citrate transport and metabolism for therapeutic applications.

Discovery of Highly Potent Solute Carrier 13 Member 5 (SLC13A5) Inhibitors for the Treatment of Hyperlipidemia

“…The aqueous layer was extracted twice with ethyl acetate, the organic layer was combined and washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated in vacuum to obtain the crude product, which was further purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50:1) to give the product as a yellow oil. (4 g, 48.57%) 1 (9). A 250 mL Three-neck flask with a magnetic stirrer was charged with EtOAc (5.01 g,56.9 mmol) and THF (60 mL).…”

“…This intolerance, characterized by musculoskeletal side effects in 7–29% of patients, compromises adherence to recommended dosages and necessitates alternative lipid-lowering therapies . Citrate plays a central role in linking glucose and lipid metabolism, acting as a key precursor and regulator of de novo lipogenesis (DNL) . The intracellular citrate concentration is a critical determinant of DNL rates; thus, targeting citrate transport and metabolism has emerged as a promising lipid-lowering strategy.…”

“…The recent approval of Bempedoic Acid (ETC-1002), an ACLY inhibitor for hypercholesterolemia, epitomizes the potential of this approach . This milestone accentuates the therapeutic value of modulating citrate transport and metabolism and serves as a catalyst for the development of small molecule inhibitors targeting key proteins within this pathway …”

“…8 Citrate plays a central role in linking glucose and lipid metabolism, acting as a key precursor and regulator of de novo lipogenesis (DNL). 9 The intracellular citrate concentration is a critical determinant of DNL rates; thus, targeting citrate transport and metabolism has emerged as a promising lipid-lowering strategy. The recent approval of Bempedoic Acid (ETC-1002), an ACLY inhibitor for hypercholesterolemia, epitomizes the potential of this approach.…”

“…10 This milestone accentuates the therapeutic value of modulating citrate transport and metabolism and serves as a catalyst for the development of small molecule inhibitors targeting key proteins within this pathway. 9 The sodium-coupled citrate transporter (NaCT), classified under the SLC13 family, is regulated by metabolic statedependent pathways, 11 which are sensitive to hormonal and nutritional changes. 11,12 Selective inhibition of SLC13A5 in rodent livers led to marked reductions in hepatic lipid levels, plasma triglycerides, and enhanced insulin sensitivity.…”