Caractérisation et études précliniques d'un nouvel inhibiteur naturel de MCL-1

Proteins of the BCL-2 family play a major role in cellular homeostasis since they regulate apoptotic cell death through dynamic interactions between the anti- and pro-apoptotic members. Over-expression of anti-apoptotic members (BCL-2, BCL-xL, MCL-1...), and particulary MCL-1, participates in the development of tumors as well as in their resistance to chemotherapy or radiotherapy treatments. Synthetic inhibitors targeting this anti-apoptotic protein have therefore been developed, some of which being currently in clinical trials. In this context, our goal is to obtain natural inhibitors of the BCL-2 family, and more specifically of MCL-1. Natural products are playing a significant role in drug discovery and development processes. Since the 1940’s, 75% of the 175 small molecules used in cancer therapy are either natural products or derivatives of natural products. We have isolated and purified a new compound called NA1-115-7, evaluated its efficiency in vitro and characterized its mechanism of action before testing it in vivo, thanks to a nano-emulsion formulation.Les protéines de la famille BCL-2 jouent un rôle majeur dans l'homéostasie cellulaire de par leur implication dans le processus apoptotique qui se fait à travers des interactions dynamiques entre les membres pro- et anti-apoptotiques composant cette famille. Parmi les membres anti-apoptotiques, MCL-1 est très fréquemment surexprimé dans les tumeurs où il est impliqué dans leur développement tout comme dans les résistances aux traitements de chimiothérapies ou de radiothérapies. Des inhibiteurs synthétiques ciblant cette protéine anti-apoptotique ont déjà été développés, certains étant même en évaluation clinique. Dans ce contexte, notre but était de développer un inhibiteur de MCL-1 naturel. Les produits naturels joue un rôle très important dans le développement de nouvelles molécules thérapeutiques. En effet, depuis les années 1940, 75% des 175 molécules utilisées dans le traitement du cancer sont soit des molécules naturelles, soit des dérivés de molécules naturelles. Nous avons donc isolé et purifié un nouveau composé, le NA1-115-7 puis nous avons évalué son efficacité in vitro, son mécanisme d'action et pour finir, nous l'avons testé in vivo grâce à l'utilisation de nano-émulsions

Characterization and Preclinical Studies of a New Natural Inhibitor of MCL-1

Les protéines de la famille BCL-2 jouent un rôle majeur dans l'homéostasie cellulaire de par leur implication dans le processus apoptotique qui se fait à travers des interactions dynamiques entre les membres pro- et anti-apoptotiques composant cette famille. Parmi les membres anti-apoptotiques, MCL-1 est très fréquemment surexprimé dans les tumeurs où il est impliqué dans leur développement tout comme dans les résistances aux traitements de chimiothérapies ou de radiothérapies. Des inhibiteurs synthétiques ciblant cette protéine anti-apoptotique ont déjà été développés, certains étant même en évaluation clinique. Dans ce contexte, notre but était de développer un inhibiteur de MCL-1 naturel. Les produits naturels joue un rôle très important dans le développement de nouvelles molécules thérapeutiques. En effet, depuis les années 1940, 75% des 175 molécules utilisées dans le traitement du cancer sont soit des molécules naturelles, soit des dérivés de molécules naturelles. Nous avons donc isolé et purifié un nouveau composé, le NA1-115-7 puis nous avons évalué son efficacité in vitro, son mécanisme d'action et pour finir, nous l'avons testé in vivo grâce à l'utilisation de nano-émulsions.Proteins of the BCL-2 family play a major role in cellular homeostasis since they regulate apoptotic cell death through dynamic interactions between the anti- and pro-apoptotic members. Over-expression of anti-apoptotic members (BCL-2, BCL-xL, MCL-1...), and particulary MCL-1, participates in the development of tumors as well as in their resistance to chemotherapy or radiotherapy treatments. Synthetic inhibitors targeting this anti-apoptotic protein have therefore been developed, some of which being currently in clinical trials. In this context, our goal is to obtain natural inhibitors of the BCL-2 family, and more specifically of MCL-1. Natural products are playing a significant role in drug discovery and development processes. Since the 1940’s, 75% of the 175 small molecules used in cancer therapy are either natural products or derivatives of natural products. We have isolated and purified a new compound called NA1-115-7, evaluated its efficiency in vitro and characterized its mechanism of action before testing it in vivo, thanks to a nano-emulsion formulation

Drimane derivatives as the first examples of covalent BH3-mimetics that target MCL-1

International audienceDrimane sesquiterpenoid dialdehydes are natural compounds with antiproliferative properties. Nevertheless, their mode of action has not yet been discovered. In this publication, we have demonstrated that various drimanes are potent inhibitors of MCL-1 and BCL-xL, two proteins of the BCL-2 family that are overexpressed in various cancers, including lymphoid malignancies. Subtle changes in their structure significantly modified their activity on the target proteins. The two most active compounds are MCL-1 selective and bind in the BH3 binding groove of the protein. Complementary studies, by NMR and mass spectrometry analyses but also synthesis showed that they are covalent inhibitors of MCL-1, via the formation of a pyrrole adduct. In addition, cytotoxic assays revealed that these two compounds show a cytotoxic selectivity for BL2, a MCL-1/BCL-xL dependent cell line and induce apoptosis

In vitro evaluation of NA1-115-7-loaded nanoemulsions, an MCL-1-specific inhibitor of natural origin, intended to treat B-cell lymphoproliferative disorders after oral administration

International audienceMCL-1, an anti-apoptotic member of the BCL-2 protein family, is overexpressed in many types of cancer and contributes to chemotherapy resistance. The drimane derivative NA1-115-7 is a natural compound isolated from Zygogynum pancheri that can be considered as a very promising lead for treating MCL-1-dependent hematological malignancies. As this drug suffers from low stability in acidic conditions and poor aqueous solubility, we evaluated the potential oral use of NA1-115-7 by encapsulating it in lipid nanoemulsions (NA-NEs) prepared by spontaneous emulsification. NA-NEs showed a particle size of 41.9 ± 2.2 nm, PDI of 0.131 ± 0.016, zeta potential of-5.8 ± 3.4 mV, encapsulation efficiency of approximately 100 % at a concentration of 24 mM. The stability of NA-1-115-7 was sixfold higher than that of the unencapsulated drug in simulated gastric fluid. NA-NEs significantly restored apoptosis and halved the effective doses of NA1-115-7 on BL2, a Burkitt lymphoma cell line, without toxicity in normal cells. Such a drug-delivery system appears to be particularly interesting for the oral administration of NA1-115-7, as it improves its solubility and stability, as well as efficacy, by reducing the therapeutic dose, making it possible to further consider in-vivo studies of this promising drug in BL2 xenografted mice

NA1—115—7, from Zygogynum pancheri, is a new selective MCL-1 inhibitor inducing the apoptosis of hematological cancer cells but non-toxic to normal blood cells or cardiomyocytes

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