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First-in-class drugs to target membrane lipids

Overview and pipeline

Our catalogue of melitherapy-based molecules in development and clinical trials

Thanks to our innovative know-how, we design novel synthetic fatty acid molecules that target the cell membrane to modulate specific signaling pathways. This structure-function based drug design is the foundation of a prolific discovery engine that has allowed us to develop a dynamic and promising pipeline of products — proposing alternative therapeutic strategies for a number of important conditions such as cancer, central nervous system diseases or metabolic disorders.

PIPELINE

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LAM561 in cancer

First-in-class anticancer drug acting through cell membrane modification

LAM561 (2-hydroxyoleic acid) is a synthetic derivative of oleic acid which can be taken orally and is able to reach cells in the brain by crossing the Blood Brain Barrier. This drug alters the composition of the plasma membrane in cancer cells, reducing the activity of membrane-associated signaling proteins that are known to promote tumor growth. Administering LAM561 shows promising results in the treatment of aggressive brain tumors, glioblastomas.

Mechanism and studied effects

Inside the cell, LAM561 is an activator of sphingomyelin synthase 1 (SMS1), a key enzyme that regulates phospholipid concentrations, particularly sphingolipids, at the plasma membrane. Membrane lipid composition and organization is known to be significantly altered in cancer cells and it has been observed that these changes increase recruitment to the cell membrane of proliferation signaling proteins, such as K-Ras. Aberrant activity of Ras-associated proliferative signaling pathways is found in at least one third of all human cancers. LAM561 induces translocation of K-Ras from its active domain in the plasma membrane, inactivating key Ras-dependent proliferation pathways (like Ras/MAPK, Pi3K/AKT/mTOR or PKC/Cyclin CDK). This causes endoplasmic reticulum stress, cell cycle arrest and eventually selective death of cancer cells in approximately 50% of the human cancer cell lines we have studied, and a similar proportion of patients treated with LAM561.

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LAM226 in Alzheimer’s disease

Omega-3 lipid derivative which specifically targets neuronal membranes

LAM226 is a modified natural fatty acid (DHA derivative) which acts selectively on neurons, due to the specific omega-3 transporters present in neuronal membranes. In studies with mice models of Alzheimer’s disease, this drug has demonstrated recovery of cognitive abilities and recovery of healthy brain biomarkers.

Mechanism and studied effects

LAM226 is a potent dose-dependent inhibitor of Tau phosphorylation (both in vitro and in vivo) as determined in differentiated SH-SY5Y cells and in brain samples of transgenic 5xFAD mice with Familiar Alzheimer´s Disease). Treatment of 5xFAD mice with LAM226 (15 mg/kg daily for 3 months) improved the mice’s performance on a computer-assisted-radial maze exercise, used to measure cognitive rehabilitation. This positive behavioral effect correlated with recovery of healthy brain biomarkers and restoration of synaptic protein expression (synaptophysin and SNAP25) in the hippocampus. Concomitant with these effects, a loss of the total brain Aβ amyloid load was observed. In addition, in vitro studies demonstrated the capacity of LAM226 to restore viability of SH-SY5Y cells in cell culture intoxicated with Aβamyloid peptide together with significant increases in markers of protective autophagy.

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LAM204 in inflammation

Polyunsaturated fatty acid to replace steroid anti-inflammatory treatments

LAM204 is a polyunsaturated fatty acid derivative which has shown a remarkable anti-inflammatory effect in laboratory studies with animal models. Its efficacy is similar to that of steroid compounds, however its non-steroid structure suggests a lower toxicity, so this aspect has been initially assessed in preliminary studies with zebra fish, flies and mice. A collaboration with an external research group (at the University of Leon, Spain) has taken place to explore the potential effect of LAM2014 in an animal model of ischemic lesion following brain stroke, with promising results.

Mechanism and studied effects

LAM204 is a polyunsaturated fatty acid derivative which has shown a remarkable anti-inflammatory effect in laboratory studies with animal models. Its efficacy is similar to that of steroid compounds, however its non-steroid structure suggests a lower toxicity, so this aspect has been initially assessed in preliminary studies with zebra fish, flies and mice. A collaboration with an external research group (at the University of Leon, Spain) is currently ongoing to explore the potential effect of LAM2014 in an animal model of ischemic lesion following brain stroke.

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New molecules

Other drugs in the pipeline

The versatility of the melitherapy approach, targeting membrane lipids of different cell types depending on the pathology, allows us to continuously investigate the therapeutic applications of new compounds.

 

LAM30171 is the latest candidate, a new fatty acid derivative currently being investigated as a potential treatment for cancer and metabolic disorders.