Lomitapide (mesylate)

Lomitapide (AEGR-733; BMS-201038) mesylate is an orally active microsomal triglyceride transfer protein (MTP) inhibitor and a selective mTORC1 inhibitor with lipid-lowering activity and BBB permeability. Lomitapide mesylate significantly reduces plasma LDL levels by blocking the assembly and secretion of very-low-density lipoprotein (VLDL). Lomitapide mesylate inhibits mTORC1 in an ATP-dependent manner, thereby inducing AMPK-independent autophagic cell death and suppressing cancer cell growth and apoptosis. Lomitapide mesylate also enhances tumor infiltration of CD8⁺ T cells. In addition, Lomitapide mesylate inhibits HDAC, improves endothelial function, effectively alleviates vascular inflammation and oxidative stress, and exerts neuroprotective effects in a cerebral ischemia/reperfusion injury model. Lomitapide mesylate can be used in research on related diseases such as colorectal cancer, breast cancer, melanoma, ischemic stroke, and familial hypercholesterolemia^[1][2][3][4]. In Vitro:Lomitapide mesylate (5 μM; 48 h) inhibits the proliferation of human HCT116, HT29 and SW480 colorectal cancer cells by reducing colony formation, and (2 μM; 96 h) inhibits the proliferation of HT29 cells overexpressing eIF4E^[1].
Lomitapide mesylate (5 μM; 24 h) induces autophagic cell death in human HCT116 and HT29 colorectal cancer cells; autophagy inhibition restores cell viability, while no apoptosis-related caspase 3/7 activity is detected^[1].
Lomitapide mesylate (5-20 μM; 48-72 h) potently inhibits the growth and induces autophagy in patient-derived human colorectal cancer organoids CRC-01 and CRC-02, and exhibits better efficacy than 5-FU (HY-90006) at equivalent concentrations^[1].
Lomitapide mesylate (0.01-1 μM; 24 h) shows no toxicity to mouse Neuro-2a cells, and improves the survival rate of OGD-injured Neuro-2a cells in a concentration-dependent manner^[2].
Lomitapide mesylate (0.01-1 μM; 24 h) shows no toxicity to primary mouse cortical neurons, and improves the cell viability of primary mouse cortical neurons injured by OGD in a concentration-dependent manner^[2].
Lomitapide mesylate restores autophagic flux and inhibits apoptosis in OGD-injured mouse Neuro-2a cells co-cultured with LPS-treated BV2 microglia, which is evidenced by the normalization of autophagy protein expression and increased Bcl-2 levels^[2].
Lomitapide mesylate significantly inhibits the migration of mouse BV2 microglial cells toward OGD-injured Neuro-2a cells^[2]. In Vivo:Lomitapide (10-50 mg/kg; intraperitoneal injection; once every 2 days for 10 days) mesylate potently inhibits the growth of colorectal cancer xenografts in BALB/c nude mice; at the dose of 20 mg/kg, it reduces the volume of HT29 tumors to approximately 38% of that in the vehicle control group, with no observed toxicity^[1].
Lomitapide (20 mg/kg; intraperitoneal injection; administered 5 times; initiated on day 10 post tumor implantation) mesylate inhibits the growth of MC38 colorectal cancer and B16-F10 melanoma in C57B6/N mice, respectively^[1].
Lomitapide (0.5 mg/kg; p.o.; once daily; for 14 consecutive days) mesylate significantly improves neurological function, reduces neuronal tissue loss by 41.05%, enhances neuronal autophagy, inhibits the migration of pro-inflammatory microglia, and increases the survival rate of mice with ischemic stroke induced by middle cerebral artery occlusion (MCAO)^[2].
Lomitapide (1 mg/kg/day; oral administration; daily dosing; for 2 consecutive weeks) mesylate improves cardiovascular function, reduces body weight and fat mass, downregulates blood glucose and lipid levels, decreases atherosclerotic plaque area, and alleviates vascular stress and inflammatory responses in obese LDLr^−/− mice^[3].