L'inhibiteur de glutaminase

Mise à jour, les inhibiteurs de glutaminase sont multiples et servent dans une variété de cancers.


déc 2015

Mutations in the oncogenic KRAS gene occur in over 90% of PDACs. KRAS is a known regulator of glutamine metabolism that renders cancer cells dependent on glutamine. Therefore, targeting glutamine metabolism may be particularly effective in treating a large portion of patients with pancreatic cancer. The first step of glutamie metabolism is the conversion of glutamine to glutamate via glutaminase. We have demonstrated that small molecule glutaminase inhibitors, such as BPTES (bis-2-[5-(phenylacetamido)-1,3,4-thiadiazol-2-yl]ethyl sulfide), block the production of glutamine in pancreatic cancer cells and attenuate growth rates in both in vitro and in vivo preclinical models. However, BPTES and other available glutaminase inhibitors are generally poorly soluble, metabolically unstable, nonselective, and/or require high doses, which reduce their efficacy and therapeutic index. Recently, nano-sized vehicles to enhance drug delivery in cancer have been approved (e.g. Doxil(r), Abraxane(r)) and have been rationalized as an approach to circumvent the stromal barrier which is a clinical challenge to drug delivery in pancreatic cancer. We recently demonstrated that nanoparticle delivery of BPTES can be safely administered and relative to free BPTES, provides dramatic improvement in tumor drug exposure and retention, resulting in greater efficacy. We have now identified several proprietary BPTES derivatives that are 10- to 100-fold more potent than BPTES and, at the same time, retain the key physicochemical properties (cLogP, PSA) required for nanoparticle encapsulation and delivery. We plan to further optimize the potency of the glutaminase inhibitors (Aim 1) and their compatibility to encapsulation (Aim 2) and evaluate their effectiveness in orthotopic xenografts from KRAS mutated patient-derived pancreatic tumors as well as KrasLSL.G12D/+; p53R172H/+; PdxCretg/+ (or KPC) mice that develop natural pancreatic tumors with characteristic stroma (Aim 3). Ultimately, we seek to translate these findings into the clinic and improve outcomes for pancreatic cancer patients. The proposal builds on the complementary strengths of the three collaborating laboratories - Slusher (small molecule drug discovery), Hanes (nanoparticle design), and Le (cancer metabolism).

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Des mutations du gène KRAS oncogénique se produisent dans plus de 90% de la PDAC . KRAS est un régulateur connu du métabolisme de la glutamine qui rend les cellules cancéreuses dépendantes de la glutamine. Par conséquent, le ciblage du métabolisme de la glutamine peut être particulièrement efficace dans le traitement d'une grande partie des patients atteints de cancer du pancréas. La première étape du métabolisme de glutamine est la conversion de la glutamine en glutamate par l'intermédiaire d'une glutaminase. Nous avons démontré que les inhibiteurs de petite molécule glutaminase, tels que les BPTES (bis-2- [5- (phénylacétamido) 2-1,3,4-thiadiazol-yl] sulfure d'éthyle),  bloquent la production de glutamine dans les cellules du cancer du pancréas et atténuer les taux de croissance à la fois in vitro et in vivo sur des modèles précliniques. Cependant, les BPTES et d'autres inhibiteurs de glutaminase disponibles sont généralement peu solubles, métaboliquement instable et non sélective, et / ou nécessitent des doses élevées, ce qui réduit leur efficacité et leur indice thérapeutique. Récemment, les véhicules de taille nanométrique pour améliorer l'administration de médicaments dans le cancer ont été approuvés (par exemple Doxil (r), Abraxane (r)) et ont été été rationalisée comme une approche pour contourner la barrière du stroma qui est un défi clinique pour l'administration de médicaments dans le cancer du pancréas . Nous avons récemment démontré que la livraison de nanoparticules de BPTES peut être administré en toute sécurité et par rapport à libérer les BPTES, apporte une amélioration spectaculaire de l'exposition au médicament et à la rétention dans la tumeur, ce qui entraîne une plus grande efficacité. Nous avons maintenant identifié plusieurs dérivéa des BPTES qui sont 10 à 100 fois plus puissant que les BPTES et, en même temps, conserver les propriétés physico-chimiques clés (ClogP, PSA) requis pour nanoparticule encapsulation en nanoparticules et pour la livraison. Nous prévoyons d'optimiser la puissance des inhibiteurs de la glutaminase (Objectif 1) et leur compatibilité à l'encapsulation (Objectif 2) et évaluer leur efficacité dans les xénogreffes orthotopique de tumeurs pancréatiques KRAS mutés provenant de patients ainsi que KrasLSL.G12D / +; p53R172H / +; PdxCretg / + (ou KPC) des souris qui développent des tumeurs pancréatiques naturelles avec stroma caractéristique (Objectif 3). En fin de compte, nous cherchons à traduire ces résultats dans la clinique et d'améliorer les résultats pour les patients atteints de cancer du . La proposition se fonde sur les forces complémentaires des trois laboratoires collaborateurs - Slusher (petite découverte de médicaments de molécule), Hanes (conception de nanoparticules), et Le (métabolisme du cancer).

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avril 2016

CB-839 (14393999-58-2) is a potent selective and orally bioavailable inhibitor of glutaminase .CB-839 displayed an antiproliferative effect in the triple-negative breast cancer cell line, HCC-1806, but no activity in the estrogen receptor-positive cell line T47D. CB-839 was able to cause proliferation arrest and apoptosis in acute myeloid leukemia cells without causing cytotoxicity against normal human CD34(+) progenitors.

Le CB-839 (14393999-58-2) est un puissant inhibiteur sélectif et biodisponible par voie orale de glutaminase .cb-839 affiche un effet antiprolifératif dans la lignée cellulaire de cancer du triple négatif, HCC-1806, mais aucune activité dans le récepteur-des oestrogènes lignée cellulaire T47D positif. CB-839 a été capable de provoquer l'arrêt de la prolifération et l'apoptose dans des cellules de leucémie myéloïde aiguë sans provoquer cytotoxicité contre CD34 humain normal (+) progéniteurs.

(Nov. 18, 2010) — Scientists at Johns Hopkins have identified a compound that could be used to starve cancers of their sugar-based building blocks. The compound, called a glutaminase inhibitor, has been tested on laboratory-cultured, sugar-hungry brain cancer cells and, the scientists say, may have the potential to be used for many types of primary brain tumors.

Les scientifiques de john Hopkins ont indentifié une molécule qui pourrait être utilisé pour affamer le cancer et lui enlever ses éléments de base pour se construire.La molécule appelé inhibiteur de glutaminase a été testé en laboratoire et on a conclu qu'elle avait le potentiel pour être utilisée sur plusieurs types de cancer primaire du

The Johns Hopkins scientists, are inventors on patent applications related to the discovery, caution that glutaminase inhibitors have not been tested in animals or humans, but their findings may spark new interest in the glutaminase pathway as a target for new therapies.

Glutaminase is an enzyme that controls how glucose-based nutrients are converted into the carbon skeleton of a cell. Additional enzymes that help construct the so-called "bricks" of the carbon skeleton are controlled by a gene called IDH1. In some brain cancer cells, IDH1 is mutated and the resulting enzyme grinds up the bricks into nutrients that feed cancer cells.

La glutaminase est un enzyme qui contrôle comment les nutriments à base de glucose sont converti en enveloppe de carbone pour la cellule. Des enzymes additionnels qui aide la construction de ce squelette de carbone sont controlé par le gène appelé IDH1. Dans les cellules du cancer du cerveau, iDH1 est muté et l'enzyme qui en résulte grignote ces éléments de base pour les changer en nutriments qui nourrissent le cancer.

"Cancer cells with mutated IDH1 become addicted to the glutaminase pathway, and this pathway may represent an Achilles' heel of cancer cells," says Chi Dang, M.D., Ph.D., The Johns Hopkins Family Professor in Oncology Research and Vice Dean for Research at the Johns Hopkins University School of Medicine. "To combat cancer, we might block the flow of materials that help create the bricks, starting with glutaminase."

Les cellules cancéreuses avec le IDH1 muté deviennent affamé du chemin cellulaire de la glutaminase et ce chemin pourrait bien un point faible du cancer.

To establish proof of the principle, the Johns Hopkins scientists and a team of chemists and geneticists at Princeton University used a glutaminase-blocking agent on cells engineered to have IDH1 mutations. The compound, called BPTES, reduced growth of the cancer cells by 30 percent. Their findings were published online November 2 in Cancer Research.

"The glutaminase inhibitor we tested does not completely stop cancer cell growth, but slows it down," says Gregory Riggins, M.D., Ph.D., the Irving J. Sherman, M.D. Professor of Neurosurgery Research and Ludwig Collaborative Laboratory Director at Johns Hopkins.

L'inhibiteur de glutaminase que nous avons essayé n'arrête pas complètement la croissance de la cellule cancéreuses mais il la ralentit.

Riggins identified BPTES' anticancer potential after screening many compounds for their glutaminase-blocking activity. BPTES was developed at Hopkins' Brain Science Institute as a potential treatment for neurological disorders and injuries that damage brain cells.

Although BPTES itself may not be useful as a therapy because of solubility problems, says Riggins, scientists at Johns Hopkins' Brain Science Institute are creating new versions of it that may overcome the problem.

"We can envision a day when patients who have IDH1 mutations are given a glutaminase inhibitor in addition to therapies that target other genomic aspects specific to their cancer," says Dang.

The mutation in IDH1, which stands for isocitrate dehydrogenase 1, was first spotted in 2008 in results from a genomewide scan of brain cancers led by Johns Hopkins scientists. It is now linked to more than 70 percent of three common types of gliomas: low-grade astrocytomas, oligodendrogliomas, and secondary glioblastomas. Researchers also have found mutations in acute myelogenous leukemias.

The mutation occurs within a single spot along a string of thousands of genetic coding letters. Among previous findings led by Johns Hopkins, patients with IDH1 mutations appear to survive at least twice as long as those without them. The researchers estimate that some 6,000 adults and children with brain cancer per year in the United States could have IDH1 mutations.

Dang and Riggins plan to test glutaminase inhibitors in cell cultures of other cancers and eventually combine the inhibitors with other gene "targeted" therapies in animal and human tests.

Both investigators also are co-inventors on a patent application on using glutaminase inhibitors for cancers with IDH1 mutations. Dang and researcher Joshua D. Rabinowitz from Princeton University are consultants for Agios Pharmaceuticals Inc. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies.

Funding for the research was provided by the Ludwig Center at Johns Hopkins, an AACR Stand Up to Cancer grant, Bayer Schering grants, the Johns Hopkins University Brain Science Institute, the Irving Sherman Neurosurgery Professorship, and the Johns Hopkins Family Professorship in Oncology Research.

(Sep. 18, 2010) — A molecule -- simply called 968 -- can starve cancer cells and the tumors they produce, says new research published by Cornell University researchers in the Colleges of Veterinary Medicine and Arts and Sciences.

Une molécule appelé simplement 968 peut affamer les cellules cancéreuses et les tumeurs qu'elles produisent .


The key to this research is the amino acid glutamine. Researchers have long believed that starving cancer cells of glutamine, which cancer cells require in larger quantities than normal cells, would help fight some cancers. Now, they have discovered a molecule that does the job: Dubbed 968 by investigators, this proof of concept molecule binds to the enzyme glutaminase to inhibit cancer growth by blocking the cancer cells' utilization of glutamine.

La clé de cette recherche c'est la glutamine, un acide aminéé Les chercheur sont longtemps cru qu'ils pourraient affamer le cancer parce queles cellules cancéreuses sont plus en demande de glutamine que les saines. Maintenant ils ont découvert une molécuel qui fait le travail et l'ont appelé 968. cette molécule se lie avec l'enzyme, la glutaminase, pour inhiber la croissance du cancer en bloquant son utilisation de de la glutamine.  



Cancer cells demand a tremendous amount of energy, says Richard Cerione, the Goldwin Smith Professor of Pharmacology and Chemical biology. The finding could lead to a new class of drugs, capable of halting cancer progression without harming normal cell growth, he said.

After discovering that 968 inhibited glutaminase and effectively shrunk tumor cells, Cerione and his research team tested the molecule to understand its effects on non-cancerous cells.

"We have effectively stopped the growth of breast cancer cells in the lab without affecting normal mammary cells," said Cerione, who is now investigating the impact of 968 on other forms of cancer, including prostate, ovarian and pancreatic cell lines. "We've validated our target. The next step will be to further the development of a classes of small molecules capable of stopping cancer cell growth in humans." To that end, Cerione and colleagues are currently working with the KensaGroup, of Ithaca, N.Y., in addition to Cerione's academic pursuits exploring the effects of 968 and glutaminase on cancer cell growth.

"Nous avons effectivement arrêté la croissance des cellules cancéreuses du dans le laboratoire sans affecter les cellules mammaires normales", a déclaré Cerione, qui examine actuellement l'impact de 968 sur les autres formes de cancer, y compris de la , des lignées de cellules de l' et du . «Nous avons validé notre objectif. La prochaine étape sera de favoriser le développement d'une classe de petites molécules capables de stopper la croissance des cellules cancéreuses chez l'homme." À cette fin, Cerione et ses collègues travaillent actuellement avec le KensaGroup, d'Ithaca, NY, en plus des activités de recherches pures sur l'exploration des effets de la 968 et du glutaminase sur la croissance des cellules cancéreuses



"Our research has highlighted a previously unrecognized connection between the cell's metabolic machinery and the signaling pathways and growth factor receptors that regulate cell growth," said Cerione. He believes there is a broader connection between metabolism and cell signaling for other areas in biology and biomedicine.

Cornell co-authors of the research include postdoctoral associate Jianbin Wang (co-first author), and senior research associates Jon Erickson (co-first author), Kristin Wilson and Sekar Ramachandran. Funding for the research: The National Institutes of Health and the Susan G. Komen Foundation.