A group of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids[1]. The SLC25 family includes carriers embedded in the inner membrane of mitochondria to secure the supply of these organelles with major metabolic intermediates and coenzymes[2].CTPI-2 is a third-generation mitochondrial citrate carrier SLC25A1 inhibitor with a KD of 3.5 μM. CTPI-2 inhibits glycolysis, PPARγ, and its downstream target the glucose transporter GLUT4. CTPI-2 halts salient alterations of NASH reverting steatosis, preventing the evolution to steatohepatitis, reducing inflammatory macrophage infiltration in the liver and adipose tissue, and starkly mitigating obesity induced by a high-fat diet. Antitumor activity. CTPI-2 is a unique regulator of glycolysis that limits the metabolic plasticity of cancer stem cells (CSCs). CTPI-2 (26 mg/kg; i.p.) inhibits tumor growth in in vivo models of non-small cell lung cancer (NSCLC)[3].CTPI-2 prevents steatohepatitis and normalizes glucose tolerance. CTPI-2 lowers the levels of circulating IL-6 while increasing anti-inflammatory IL-4 and IL-10 and also reduced the monocyte chemoattractant protein-1 and monokine-induced by interferon-γ that attract neutrophils and monocytes. CTPI-2 regulates the citrate pool, the lipogenic and the gluconeogenic pathways[4].
CTPI-2 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MOLM13 cells
20 μM, 60 μM, 80 μM
48 h
Inhibition of AML cell proliferation
Front Genet. 2023 Jan 6;13:1081262
MV-4-11 cells
20 μM, 60 μM, 80 μM
48 h
Inhibition of AML cell proliferation
Front Genet. 2023 Jan 6;13:1081262
CTPI-2 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6J mice
High-fat diet-induced obesity and NAFLD/NASH model
Intraperitoneal injection
50 mg/kg
Alternate days for 12 weeks
To evaluate the reversal effects of CTPI-2 on HFD-induced obesity, hepatic steatosis, and inflammation. Results demonstrated CTPI-2 significantly reduced body weight, liver fat accumulation, inflammatory responses, and improved glucose tolerance and insulin sensitivity.
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